HK1155745A

HK1155745A - Daa-pyridine as peripheral benzodiazepine receptor ligand for diagnostic imaging and pharmaceutical treatment

Info

Publication number: HK1155745A
Application number: HK11110119.2A
Authority: HK
Inventors: L‧莱曼; A‧蒂勒; T‧海因里希; S‧福尔默
Original assignee: 拜耳先灵医药股份有限公司
Priority date: 2008-08-06
Filing date: 2009-08-05
Publication date: 2012-05-25

Description

DAA-pyridines as peripheral benzodiazepine  receptor ligands for diagnostic imaging and drug therapy

Technical Field

The invention relates to a method for adapting¹⁸F is marked or marked by¹⁸Novel compounds labelled with F, methods of preparing such compounds, compositions comprising such compounds, kits comprising such compounds or compositions, and uses of such compounds, compositions or kits in therapy and diagnostic imaging by Positron Emission Tomography (PET).

Background

Molecular imaging has the potential to detect disease progression or therapeutic effect earlier than most traditional methods in the fields of oncology, neurology and cardiology. Among several promising molecular imaging techniques that have been developed, such as optical imaging, MRI, SPECT and PET, PET is particularly useful for drug development due to its high sensitivity and ability to provide quantitative and kinetic data.

Positron emitting isotopes include, for example, carbon, iodine, fluorine, nitrogen, and oxygen. These isotopes can replace their non-radioactive counterparts in target compounds to produce tracers for PET imaging that are biologically functional and chemically equivalent to the original molecule. Among these isotopes are, for example,¹⁸f is the most convenient labelled isotope due to its relatively long half-life (111min), which allows the preparation of diagnostic tracers and subsequent investigation of biochemical processes. In addition to this, the present invention is,¹⁸the low β + energy of F (634keV) is also advantageous.

Nucleophilic aromatic and aliphatic [ alpha ]¹⁸F]-fluorine-fluorination reaction for¹⁸F]Of importance is a fluorine-labeled radiopharmaceutical, said [2 ]¹⁸F]Fluorine labelled radiopharmaceuticals are used as in vivo imaging agents to target and visualize diseases such as solid tumors or brain diseases. Due to the fact that¹⁸The half-life of the F isotope is only about 111 minutes, so that the F isotope is used¹⁸F]A very important technical goal of fluorine-labelled radiopharmaceuticals is the rapid preparation and administration of the radioactive compound.

Some methods are known for introducing F-18 into aromatic rings (Coenen, Fluorine-18labeling methods: Features and Possibilities of Basic Reactions, (2006), in: Schubiger P.A., Friebe M., Lehmann L., (eds), PET-Chemistry-The Driving Force in molecular imaging. Springer, Berlin Heidelberg, pp.15-50). One of the recent findings is that of¹⁸F]Fluorine replaces the iodonium leaving group, comparing for example WO2005061415(a1), WO2005097713(a1), WO2007010534(a2), WO2007073200(a1) and WO2007141529(a 1).

Peripheral benzodiAza derivativesReceptors (PBRs) are expressed in most organs and their expression is reported to be increased in activated microglia in the brain, the smallest type of glial cell that serves as a Central Nervous System (CNS) immune cell. Microglia are associated with other phagocytic cells including macrophages and dendritic cells. Microglia are considered highly mobile cells that play many important roles in protecting the nervous system. Microglia are also thought to play a role in neurodegenerative diseases such as alzheimer's disease, dementia, multiple sclerosis, and amyotrophic lateral sclerosis. Microglia are responsible for producing an inflammatory response to injury (j. neuronflammation, 2004, Jul 30; 1 (1): 14.).

An important goal in designing adequate CNS-PET tracers is to optimize pharmacokinetics in the brain. Thus, the PET ligand should rapidly enter the brain in sufficient quantities. Subsequently, a large portion of these molecules should bind tightly to the target. Subsequently, these unbound molecules should be removed from the peripheral region ("wash-out" from the brain) in order to obtain an image with a high signal to background ratio.

The C-11 isotopically labeled form of PK11195(1a) has been widely used for in vivo imaging of neuroinflammation and PBR, but its signal in the brain is not high enough for stable quantitative analysis.

In addition, it has been demonstrated that a higher positron-emitting ligand, such as [ alpha ], [ beta ]¹⁸F]DPA714(1.2)、[¹¹C]DAA1106(2) (e.g., Eur J Pharmacol.1999 Apr 29; 371 (2-3): 197-¹⁸F]Development of fluoroethyl-DAA 1106(3) (e.g. j.nuclear. med., (2006), 47, 43-50) is used to make it possible to visualize the PBR: compounds 2 and 3 vs PBRHas high binding affinity and can accumulate in the brain more than [2 ]¹¹C]PK11195(1.1a)。

The patent family related to WO99/006353 claims the non-radioactive form of compound 2, while the patent family related to US6,870,069 claims compound 3.

Recently, the respective terms "2¹⁸F]FEPPA, novel [ F-18] of (4) and (5)]And [ C-11]Labeled PBR ligands (Nuclear Medicine and Biology, 35, (2008), 305-. "[¹⁸F]-FEPPA [ Compound 4]Shows moderate brain absorption [5min Standard absorption Curve (SUV) 0.6]Slow elution [ SUV 0.35 after 60min]"(from Nuclear Medicine and Biology, 35, (2008)). Thus, compound 4 produced images with relatively low signal-to-noise ratios.

Such derivatives have been covered by patent application WO2007/060157 and corresponding patent family members.

Disclosure of Invention

It would be desirable to have new F-18 labeled compounds and methods that can be used to image diseases with elevated levels of PBR receptors, particularly imaging agents and methods that are easy to implement and are capable of imaging specific levels of PBR receptors with sufficient signal to background ratio. This task is solved by the following invention (compare fig. 1):

■ the present invention provides novel compounds of formula I. If these compounds of the formula I are not¹⁸F-tag or¹⁹The label of the F-label is obtained,but contain suitable leaving groups, they are useful for synthesis¹⁸F-tag or¹⁹F-labelled starting material for the compound of formula I.¹⁹The F-labelled compounds of the formula I are synthesized¹⁸F-labelled Standard reference Compounds for Compounds of formula I (as an identification tool and quality check). The following contain a suitable leaving group and do not contain¹⁸F or¹⁹The compounds of formula I of F are also referred to as "precursor compounds having formula I". And, comprises¹⁹Those compounds of formula I which do not contain a suitable leaving group but F are also referred to as "having formula I¹⁹F standard reference compound ". And, comprises¹⁸Those compounds of formula I which do not contain a suitable leaving group and which are F are also referred to as "¹⁸F-labeled compound of formula I ".

■ the invention also provides a method of imaging a disease comprising introducing into a patient a detectable amount of¹⁸An F-labelled compound of formula I, or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.

■ the invention also provides a pharmaceutical composition for use as a medicament¹⁸F-tag or¹⁹F-labelled compounds of formula I.

■ the invention also provides diagnostic compositions comprising a radiolabeled compound, preferably¹⁸F-labelled compounds of formula I; and a pharmaceutically acceptable carrier or diluent.

■ Another aspect of the invention relates to compounds of formula I, in particular¹⁸F-tag or¹⁹Use of a F-labelled compound of formula I for the manufacture of a medicament.

■ the invention also provides a synthesis from a precursor compound having formula I¹⁸A method of F-labeling a compound of formula I.

■ the invention also provides a synthesis from a precursor compound having formula I¹⁹A method of F-labeling a compound of formula I.

■ the present invention provides novel compounds of formula VI. These compounds act as precursor compounds for the compounds of the formula IBy reacting a compound of formula IV with a compound of formula VI. The compound of formula IV can be prepared by¹⁸F-or¹⁹F-fluorinating a compound of formula V.

■ the invention also provides for the synthesis of compounds of formula IV by reacting with compounds of formula VI¹⁸A method of F-labeling a compound of formula I. The compound of formula IV can be prepared by¹⁸F-or¹⁹F-fluorinating a compound of formula V.

■ the invention also provides a kit for the preparation of a radiopharmaceutical comprising a sealed vial containing a predetermined amount of a pharmaceutically acceptable carrier

A precursor compound having the formula I, or

Compounds of formula V and VI.

■ the invention also provides kits for imaging diseases. More specifically, the compounds of the invention are useful for imaging CNS diseases including, but not limited to, inflammatory and autoimmune diseases, allergic diseases, infectious diseases and toxin-induced and ischemia-induced diseases, inflammation induced by pharmacological effects associated with pathophysiology, neurogenic inflammation, neurodegenerative diseases. In another embodiment, the compounds of the invention are used for imaging tissues, in particular tumors. Examples of inflammatory and autoimmune diseases are chronic inflammatory bowel disease (inflammatory bowel disease, crohn's disease, ulcerative colitis), arthritis, atheroma, atherosclerosis, inflammatory cardiomyopathy, pemphigus, asthma, multiple sclerosis, diabetes, type I insulin dependent diabetes mellitus, rheumatoid arthritis, lupus disease and other collagen diseases (collagenoses), graves ' disease, hashimoto's disease, "graft-versus-host disease" and transplant rejection. Examples of allergic diseases, infectious diseases and toxin-and ischemia-induced diseases are: sarcoidosis, asthma, hypersensitivity pneumonitis, sepsis, septic shock, endotoxic shock, toxic shock syndrome, toxic hepatic failure, ARDS (acute respiratory distress syndrome), eclampsia, cachexia, acute viral infections (such as mononucleosis, fulminant hepatitis) and organ injury following reperfusion. An example of pathophysiologically relevant pharmacologic effects-induced inflammation is the "first dose response" following administration of anti-T cell antibodies such as OKT 3. An example of a systemic inflammatory response of unknown origin is eclampsia. Examples of neurodegenerative diseases and neurogenic inflammation associated with PBR modulation are dementia, AIDS dementia, amyotrophic lateral sclerosis, encephalitis, neuropathic pain, creutzfeldt-jakob disease, down syndrome, diffuse lewy body disease, huntington's disease, leukoencephalopathy, encephalopathy, infectious encephalopathy, hepatic encephalopathy, multiple sclerosis, parkinson's disease, pick's disease, alzheimer's disease, frontotemporal dementia, hippocampal sclerosis, cysticercosis, epilepsy, stroke, ischemia, brain tumors, depression, schizophrenia, drug abuse. The invention therefore also relates to the use of the imaging compounds for the diagnosis of these diseases, as well as for therapy stratification and therapy monitoring.

In a preferred embodiment, the compounds of the invention are used for imaging multiple sclerosis, alzheimer's disease, frontotemporal dementia, dementia associated with lewy bodies, leukoencephalopathy, epilepsy, neuropathic pain, amyotrophic lateral sclerosis, parkinson's disease, encephalopathy, brain tumors, depression, drug abuse, chronic inflammatory bowel disease, atheroma, atherosclerosis, arthritis, rheumatoid arthritis, pharmacologically induced inflammation, systemic inflammation of unclear origin.

In a more preferred embodiment, the compounds of the invention are used for imaging of multiple sclerosis, alzheimer's disease, amyotrophic lateral sclerosis, parkinson's disease, leukoencephalopathy, encephalopathy, epilepsy, brain tumors, drug abuse, chronic inflammatory bowel disease, atheroma, rheumatoid arthritis, pharmacologically induced inflammation and systemic inflammation of unclear origin.

JP 2000-001476 describes similar compounds disclosed herein and their use in the treatment of diseases.

Detailed Description

In a first aspect, the present invention relates to compounds of formula I, including all isomeric forms of said compounds, including but not limited to enantiomers and diastereomers and racemic mixtures, and any pharmaceutically acceptable salts, esters, amides, complexes or prodrugs thereof,

wherein

At each occurrence, R¹And R²Independently and independently selected from the group consisting of (G)³) Aryl, substituted (G)³) Aryl group, (G)³-(C₁-C₈) Alkyl) aryl, (G)³-(C₁-C₈) Alkoxy) aryl, (G)³-(C₂-C₈) Alkynyl) aryl, (G)³-(C₂-C₈) Alkenyl) aryl, substituted (G)³-(C₁-C₈) Alkyl) aryl, substituted (G)³-(C₁-C₈) Alkoxy) aryl, substituted (G)³-(C₂-C₈) Alkynyl) aryl and substituted (G)³-(C₂-C₈) Alkenyl) aryl;

at each occurrence, G¹、G²And G³Independently and each selected from the group comprising hydrogen and L,

provided that the compound of formula I comprises exactly one L;

l is selected from the group consisting of R³、[¹⁸F]Fluorine and [2 ]¹⁹F]A group of fluorine;

R³is a leaving group;

R⁶selected from the group consisting of hydrogen, halogen, trifluoromethyl, (C)₁-C₅) Alkyl, (C)₂-C₅) Alkynyl group), (C)₂-C₅) Alkenyl and (C)₁-C₅) A group of alkoxy groups;

wherein n is an integer from 0 to 6, preferably from 0 to 2, more preferably from 0 to 1, even more preferably 1.

In a preferred embodiment, R in formula I is present at each occurrence¹And R²Independently and independently selected from the group consisting of (G)³) Phenyl, (G)³-(C₁-C₅) Alkyl) phenyl, (G)³-(C₁-C₅) Alkoxy) phenyl, (G)³-(C₂-C₅) Alkynyl) phenyl, (G)³-(C₂-C₅) Alkenyl) phenyl, substituted (G)³) Phenyl, substituted (G)³-(C₁-C₅) Alkyl) phenyl, substituted (G)³-(C₁-C₅) Alkoxy) phenyl, substituted (G)³-(C₂-C₅) Alkynyl) phenyl and substituted (G)³-(C₂-C₅) Alkenyl) phenyl;

in a more preferred embodiment, at each occurrence, R in formula I¹And R²Independently and independently selected from the group consisting of (R)⁴)(R⁵)(G³) Phenyl, (R)⁴)(R⁵)(G³-(C₁-C₄) Alkyl) phenyl, (R)⁴)(R⁵)(G³-(C₁-C₄) Alkoxy) phenyl, (R)⁴)(R⁵)(G³-(C₂-C₄) Alkenyl) phenyl and (R)⁴)(R⁵)(G³-(C₂-C₄) Alkynyl) phenyl;

in an even more preferred embodiment, at each occurrence, R in formula I¹And R²Independently and independently selected from the group consisting of (R)⁴)(R⁵)(G³) Phenyl, (R)⁴)(R⁵)(G³-(C₂-C₃) Alkyl) phenyl and (R)⁴)(R⁵)(G³-(C₂-C₃) Alkoxy) phenyl;

in a most preferred embodiment, R in formula I at each occurrence¹And R²Independently and independently selected from the group consisting of (R)⁴)(R⁵)(G³) Phenyl and (R)⁴)(R⁵)(G³-(C₂-C₃) Alkoxy) phenyl;

wherein, at each occurrence, R⁴And R⁵Independently and independently selected from the group consisting of hydrogen, halogen, trifluoromethyl, (C)₁-C₅) Alkyl, (C)₂-C₅) Alkynyl group), (C)₂-C₅) Alkenyl and (C)₁-C₅) A group of alkoxy groups;

in a preferred embodiment, at each occurrence, R⁴And R⁵Independently and each selected from the group comprising hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl;

in an even more preferred embodiment, at each occurrence, R⁴And R⁵Independently and each selected from the group comprising hydrogen, fluoro, methyl and methoxy;

in a preferred embodiment, R⁶Selected from the group comprising hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl;

in a more preferred embodiment, R⁶Selected from the group comprising hydrogen, fluorine, chlorine and methyl;

in an even more preferred embodiment, R⁶Selected from the group comprising hydrogen and chlorine;

in a most preferred embodiment, R⁶Is hydrogen;

in one embodiment, L is [ alpha ]¹⁸F]Fluorine;

in one embodiment, L is [ alpha ]¹⁹F]Fluorine;

in one embodiment, L is R³；

In a preferred embodiment, R³Is selected from the group consisting of⁺(aryl) (X)^-)、-I⁺(heteroaryl) (X)^-) Nitro, -N⁺(Me)₃(X^-) Halogen, in particular chlorine, bromine and iodine, mesyloxy, methylA group of benzenesulfonyloxy, trifluoromethylsulfonyloxy, nona-fluorobutylsulfonyloxy, (4-bromo-phenyl) sulfonyloxy, (4-nitro-phenyl) sulfonyloxy, (2-nitro-phenyl) sulfonyloxy, (4-isopropyl-phenyl) sulfonyloxy, (2, 4, 6-tri-isopropyl-phenyl) sulfonyloxy, (2, 4, 6-trimethyl-phenyl) sulfonyloxy, (4-tert-butyl-phenyl) sulfonyloxy and (4-methoxy-phenyl) sulfonyloxy;

in a more preferred embodiment, R³Selected from the group consisting of nitro, -N⁺(Me)₃(X^-) Halogen, in particular chlorine, bromine and iodine, mesyloxy, tosyloxy, trifluoromethylsulfonyloxy, nonafluorobutylsulfonyloxy, (4-bromo-phenyl) sulfonyloxy, (4-nitro-phenyl) sulfonyloxy, (2-nitro-phenyl) sulfonyloxy, (4-isopropyl-phenyl) sulfonyloxy, (2, 4, 6-tri-isopropyl-phenyl) sulfonyloxy, (2, 4, 6-trimethyl-phenyl) sulfonyloxy, (4-tert-butyl-phenyl) sulfonyloxy and (4-methoxy-phenyl) sulfonyloxy;

in an even more preferred embodiment, R³Selected from the group consisting of nitro, -N⁺(Me)₃(X^-) Chlorine, bromine, methanesulfonyloxy and toluenesulfonyloxy;

wherein X^-Selected from the group consisting of inorganic acid anions and organic acid anions;

in a preferred embodiment, X^-Selected from the group consisting of CF₃S(O)₂O^-、C₄F₉S(O)₂O^-、CF₃COO^-、H₃CCOO^-Iodine anion, bromine anion, chlorine anion, perchlorate anion (ClO)₄ ^-) And phosphate anions;

in an even more preferred embodiment, X^-Selected from the group consisting of CF₃S(O)₂O^-、C₄F₉S(O)₂O^-Iodine anion, bromine anion and CF₃COO^-A group of (1);

the term "anion of an inorganic or organic acid" as used herein refers to the corresponding base of an inorganic acid including, but not limited to, acids such as carbonic, nitric or sulfuric acid, hydrochloric, hydrobromic, hydroiodic, phosphoric, perchloric; or the corresponding bases of suitable organic acids including, but not limited to, acids such as aliphatic, alicyclic, aromatic, araliphatic (araliphatic) and heterocyclic carboxylic and sulfonic acids, examples of which are formic, acetic, trifluoroacetic, propionic, succinic, glycolic, gluconic, lactic, malic, fumaric, pyruvic, benzoic, anthranilic, methanesulfonic (mesylic) acid, fumaric, salicylic, phenylacetic, mandelic, pamoic, methanesulfonic (methansulfonic acid), ethanesulfonic, benzenesulfonic, pantothenic (pantothenic) acid, toluenesulfonic, 1,2, 2, 3, 3, 4, 4, 4-nonafluorobutane-1-sulfonic acid, and sulfanilic acid.

The term "corresponding base" as used herein refers to an acid which dissociates after giving a proton.

In one embodiment of formula I, L is R³(ii) a These are the "precursor compounds" described above.

Preferred "precursor compounds having formula I" are:

2- [2- ({ acetyl [2- (4-fluorophenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] ethyl methanesulfonate

2- [2- ({ acetyl [2- (4-iodophenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] ethyl methanesulfonate

2- [2- ({ acetyl [ 2-phenoxypyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] ethyl methanesulfonate

2- [2- ({ acetyl [2- (2-fluorophenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] ethyl methanesulfonate

2- [2- ({ acetyl [2- (4-chlorophenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] ethyl methanesulfonate

2- [2- ({ acetyl [2- (4-methoxyphenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] ethyl methanesulfonate

3- [2- ({ acetyl [2- (4-fluorophenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] propyl 4-methylbenzenesulfonate

3- [2- ({ acetyl [2- (4-iodophenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] propyl 4-methylbenzenesulfonate

3- [2- ({ acetyl [2- (phenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] propyl 4-methylbenzenesulfonate

3- [2- ({ acetyl [2- (2-fluorophenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] propyl 4-methylbenzenesulfonate

3- [2- ({ acetyl [2- (4-chlorophenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] propyl 4-methylbenzenesulfonate

3- [2- ({ acetyl [2- (4-methoxyphenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] propyl 4-methylbenzenesulfonate

N- (6-chloro-2-phenoxypyridin-3-yl) -N- (2, 5-dimethoxybenzyl) acetamide

N- [ 6-chloro-2- (4-chlorophenoxy) pyridin-3-yl ] -N- (2, 5-dimethoxybenzyl) acetamide

N- [ 6-chloro-2- (4-methoxyphenoxy) pyridin-3-yl ] -N- (2, 5-dimethoxybenzyl) acetamide

N- [ 6-chloro-2- (2, 3-dimethylphenoxy) pyridin-3-yl ] -N- (2, 5-dimethoxybenzyl) acetamide

N- [ 6-chloro-2- (4-iodophenoxy) pyridin-3-yl ] -N- (2, 5-dimethoxybenzyl) acetamide

N- [ 6-chloro-2- (4-fluorophenoxy) pyridin-3-yl ] -N- (2, 5-dimethoxybenzyl) acetamide

N- (6-chloro-2-phenoxypyridin-3-yl) -N- (2-methoxybenzyl) acetamide

N- [ 6-chloro-2- (4-chlorophenoxy) pyridin-3-yl ] -N- (2-methoxybenzyl) acetamide

N- [ 6-chloro-2- (4-methoxyphenoxy) pyridin-3-yl ] -N- (2-methoxybenzyl) acetamide

N- [ 6-chloro-2- (2, 3-dimethylphenoxy) pyridin-3-yl ] -N- (2-methoxybenzyl) acetamide

N- [ 6-chloro-2- (4-iodophenoxy) pyridin-3-yl ] -N- (2-methoxybenzyl) acetamide

N- [ 6-chloro-2- (4-fluorophenoxy) pyridin-3-yl ] -N- (2-methoxybenzyl) acetamide

N- (6-bromo-2-phenoxypyridin-3-yl) -N- (2, 5-dimethoxybenzyl) acetamide

N- [ 6-bromo-2- (4-chlorophenoxy) pyridin-3-yl ] -N- (2, 5-dimethoxybenzyl) acetamide

N- [ 6-bromo-2- (4-methoxyphenoxy) pyridin-3-yl ] -N- (2, 5-dimethoxybenzyl) acetamide

N- [ 6-bromo-2- (2, 3-dimethylphenoxy) pyridin-3-yl ] -N- (2, 5-dimethoxybenzyl) acetamide

N- [ 6-bromo-2- (4-iodophenoxy) pyridin-3-yl ] -N- (2, 5-dimethoxybenzyl) acetamide

N- [ 6-bromo-2- (4-fluorophenoxy) pyridin-3-yl ] -N- (2, 5-dimethoxybenzyl) acetamide

N- (6-bromo-2-phenoxypyridin-3-yl) -N- (2-methoxybenzyl) acetamide

N- [ 6-bromo-2- (4-chlorophenoxy) pyridin-3-yl ] -N- (2-methoxybenzyl) acetamide

N- [ 6-bromo-2- (4-methoxyphenoxy) pyridin-3-yl ] -N- (2-methoxybenzyl) acetamide

N- [ 6-bromo-2- (2, 3-dimethylphenoxy) pyridin-3-yl ] -N- (2-methoxybenzyl) acetamide

N- [ 6-bromo-2- (4-iodophenoxy) pyridin-3-yl ] -N- (2-methoxybenzyl) acetamide

N- [ 6-bromo-2- (4-fluorophenoxy) pyridin-3-yl ] -N- (2-methoxybenzyl) acetamide

In another embodiment of formula I, L is [ alpha ]¹⁸F]Fluorine, these are¹⁸F-labeled compounds having formula I.

Preferred "F-18 labeled compounds of formula I" are:

N-{2-[2-(¹⁸F) fluoroethoxy group]-5-methoxybenzyl } -N- [2- (4-fluorophenoxy) pyridin-3-yl]Acetamide

N-{2-[2-(¹⁸F) Fluoroethoxy group]-5-methoxybenzyl } -N- [2- (4-iodophenoxy) pyridin-3-yl]Acetamide

N-[2-(2-(¹⁸F) Fluoroethoxy) -5-methoxybenzyl]-N- [2- (phenoxy) pyridin-3-yl]Acetamide

N-[2-(2-(¹⁸F) Fluoroethoxy) -5-methoxybenzyl]-N- [2- (2-fluorophenoxy) pyridin-3-yl]Acetamide

N- [2- (4-chlorophenoxy) pyridin-3-yl]-N-[2-(2-(¹⁸F) Fluoroethoxy) -5-methoxybenzyl]Acetamide

N-[2-(2-(¹⁸F) Fluoroethoxy) -5-methoxybenzyl]-N- [2- (4-methoxyphenoxy) pyridin-3-yl]Acetamide

N-[2-(3-(¹⁸F) Fluoropropoxy) -5-methoxybenzyl]-N- [2- (4-fluorophenoxy) pyridin-3-yl]Acetamide

N-[2-(3-(¹⁸F) Fluoropropoxy) -5-methoxybenzyl]-N- [2- (4-iodophenoxy) pyridin-3-yl]Acetamide

N-[2-(3-(¹⁸F) Fluoropropoxy) -5-methoxybenzyl]-N- [2- (phenoxy) pyridin-3-yl]Acetamide

N-[2-(3-(¹⁸F) Fluoropropoxy) -5-methoxybenzyl]-N- [2- (2-fluorophenoxy) pyridin-3-yl]Acetamide

N- [2- (4-chlorophenoxy) pyridin-3-yl]-N-[2-(3-(¹⁸F) Fluoropropoxy) -5-methoxybenzyl]Acetamide

N-[2-(3-(¹⁸F) Fluoropropoxy) -5-methoxybenzyl]-N- [2- (4-methoxyphenoxy) pyridin-3-yl]Acetamide

N-{2-[(¹⁸F) Fluoromethoxy group]-5-methoxybenzyl]-N- [2- (4-fluorophenoxy) pyridin-3-yl]Acetamide

N-{2-[(¹⁸F) Fluoromethoxy group]-5-methoxybenzyl]-N- [2- (4-iodophenoxy) pyridin-3-yl]Acetamide

N-[2-((¹⁸F) Fluoromethoxy) -5-methoxybenzyl]-N- [2- (phenoxy) pyridin-3-yl]Acetamide

N-[2-((¹⁸F) Fluoromethoxy) -5-methoxybenzyl]-N- [2- (2-fluorophenoxy) pyridin-3-yl]Acetamide

N- [2- (4-chlorophenoxy) pyridin-3-yl]-N-[2-((¹⁸F) Fluoromethoxy) -5-methoxybenzyl]Acetamide

N-[2-((¹⁸F) Fluoromethoxy) -5-methoxybenzyl]-N- [2- (4-methoxyphenoxy) pyridin-3-yl]Acetamide

N- (2, 5-Dimethoxybenzyl) -N- (6- (18F) fluoro-2-phenoxypyridin-3-yl) acetamide

N- [2- (4-chlorophenoxy) -6- (18F) fluoropyridin-3-yl) -N- (2, 5-dimethoxybenzyl) acetamide

N- (2, 5-Dimethoxybenzyl) -N- [6- (18F) fluoro-2- (4-methoxyphenoxy) pyridin-3-yl ] acetamide

N- (2, 5-Dimethoxybenzyl) -N- [2- (2, 3-dimethylphenoxy) -6- (18F) fluoropyridin-3-yl ] acetamide

N- (2, 5-Dimethoxybenzyl) -N- [6- (18F) fluoro-2- (4-iodophenoxy) pyridin-3-yl ] acetamide

N- (2, 5-Dimethoxybenzyl) -N- [6- (18F) fluoro-2- (4-fluorophenoxy) pyridin-3-yl ] acetamide

N- (2-methoxybenzyl) -N- (6- (18F) fluoro-2-phenoxypyridin-3-yl) acetamide

N- [2- (4-chlorophenoxy) -6- (18F) fluoropyridin-3-yl) -N- (2-methoxybenzyl) acetamide

N- (2-methoxybenzyl) -N- [6- (18F) fluoro-2- (4-methoxyphenoxy) pyridin-3-yl ] acetamide

N- (2-methoxybenzyl) -N- [2- (2, 3-dimethylphenoxy) -6- (18F) fluoropyridin-3-yl ] acetamide

N- (2-methoxybenzyl) -N- [6- (18F) fluoro-2- (4-iodophenoxy) pyridin-3-yl ] acetamide

N- (2-methoxybenzyl) -N- [6- (18F) fluoro-2- (4-fluorophenoxy) pyridin-3-yl ] acetamide

In another embodiment of formula I, L is [ alpha ]¹⁹F]Fluorine, these are the "standard reference compounds having formula I" described above.

Preferred "standard reference compounds having formula I" are:

n- [2- (2-fluoroethoxy) -5-methoxybenzyl ] -N- [2- (4-fluorophenoxy) pyridin-3-yl ] acetamide

N- [2- (2-fluoroethoxy) -5-methoxybenzyl ] -N- [2- (4-iodophenoxy) pyridin-3-yl ] acetamide

N- [2- (2-fluoroethoxy) -5-methoxybenzyl ] -N- [2- (phenoxy) pyridin-3-yl ] acetamide

N- [2- (2-fluoroethoxy) -5-methoxybenzyl ] -N- [2- (2-fluorophenoxy) pyridin-3-yl ] acetamide

N- [2- (4-chlorophenoxy) pyridin-3-yl ] -N- [2- (2-fluoroethoxy) -5-methoxybenzyl ] acetamide

N- [2- (2-fluoroethoxy) -5-methoxybenzyl ] -N- [2- (4-methoxyphenoxy) pyridin-3-yl ] -acetamide

N- {2- [3- (fluoropropoxy) -5-methoxybenzyl } -N- [2- (4-fluorophenoxy) pyridin-3-yl ] acetamide

N- {2- [3- (Fluoropropoxy) -5-methoxybenzyl } -N- [2- (4-iodophenoxy) pyridin-3-yl ] acetamide

N- [2- (3- (fluoropropoxy) -5-methoxybenzyl ] -N- [2- (phenoxy) pyridin-3-yl ] -acetamide

N- [2- (3- (fluoropropoxy) -5-methoxybenzyl ] -N- [2- (2-fluorophenoxy) pyridin-3-yl ] -acetamide

N- [2- (4-chlorophenoxy) pyridin-3-yl ] -N- [2- (3-fluoropropoxy) -5-methoxybenzyl ] -acetamide

N- [2- (3- (fluoropropoxy) -5-methoxybenzyl ] -N- [2- (4-methoxyphenoxy) pyridin-3-yl ] -acetamide

N- [2- (fluoromethoxy) -5-methoxybenzyl ] -N- [2- (4-fluorophenoxy) pyridin-3-yl ] -acetamide

N- [2- (fluoromethoxy) -5-methoxybenzyl ] -N- [2- (4-iodophenoxy) pyridin-3-yl ] -acetamide

N- [2- (fluoromethoxy) -5-methoxybenzyl ] -N- [2- (phenoxy) pyridin-3-yl ] -acetamide

N- [2- (fluoromethoxy) -5-methoxybenzyl ] -N- [2- (2-fluorophenoxy) pyridin-3-yl ] -acetamide

N- [2- (4-chlorophenoxy) pyridin-3-yl ] -N- [2- (fluoromethoxy) -5-methoxybenzyl ] -acetamide

N- [2- (fluoromethoxy) -5-methoxybenzyl ] -N- [2- (4-methoxyphenoxy) pyridin-3-yl ] -acetamide

N- (2, 5-dimethoxybenzyl) -N- (6-fluoro-2-phenoxypyridin-3-yl) acetamide

N- [2- (4-chlorophenoxy) -6-fluoropyridin-3-yl ] -N- (2, 5-dimethoxybenzyl) acetamide

N- (2, 5-Dimethoxybenzyl) -N- (6-fluoro-2- (4-methoxyphenoxy) pyridin-3-yl ] acetamide

N- (2, 5-Dimethoxybenzyl) -N- [2- (2, 3-dimethylphenoxy) -6-fluoropyridin-3-yl ] acetamide

N- (2, 5-dimethoxybenzyl) -N- [ 6-fluoro-2- (4-iodophenoxy) pyridin-3-yl ] acetamide

N- (2, 5-dimethoxybenzyl) -N- [ 6-fluoro-2- (4-fluorophenoxy) pyridin-3-yl ] acetamide

N- (2-methoxybenzyl) -N- (6-fluoro-2-phenoxypyridin-3-yl) acetamide

N- [2- (4-chlorophenoxy) -6-fluoropyridin-3-yl ] -N- (2-methoxybenzyl) acetamide

N- (2-methoxybenzyl) -N- (6-fluoro-2- (4-methoxyphenoxy) pyridin-3-yl ] acetamide

N- (2-methoxybenzyl) -N- [2- (2, 3-dimethylphenoxy) -6-fluoropyridin-3-yl ] acetamide

N- (2-methoxybenzyl) -N- [ 6-fluoro-2- (4-iodophenoxy) pyridin-3-yl ] acetamide

N- (2-methoxybenzyl) -N- [ 6-fluoro-2- (4-fluorophenoxy) pyridin-3-yl ] acetamide

R³Are leaving groups known or apparent to those skilled in the art and derived from, but not limited to, those described or named in the following references: synthesis (1982), p.85-125, Table 2 (p.86; (the last item of Table 2 should be modified to: "n-C₄F₉S(O)₂-O-nonaflatat "instead of" n-C₄H₉S(O)₂-O-nonaflat”)，Carey and Sundberg，OrganischeSynthese，(1995)，page 279-281，table 5.8；or Netscher，Recent Res.Dev.Org.Chem.，2003，7，71-83，scheme 1，2，10 and 15 and others)。(Coenen，Fluorine-18 Labeling Methods：Features and Possibilities of Basic Reactions，(2006)，in：Schubiger P.A.，Friebe M.，Lehmann L.，(eds)，PET-Chemistry-TheDriving Force in Molecular Imaging.Springer，Berlin Heidelberg，pp.15-50，explicitly：scheme 4 pp.25，scheme 5 pp 28，table 4 pp 30，Fig 7 pp 33)。

It will be clear that wherever in this specification the terms "aryl", "heteroaryl" or any other term referring to aromatic systems are used, this also includes the possibility that such aromatic systems are substituted by one or more suitable substituents, such as OH, halogen, (C)₁-C₆) Alkyl, CF₃、CN、(C₁-C₆) Alkenyl, (C)₁-C₆) Alkynyl, (C)₁-C₆) Alkoxy, NH₂、NO₂、S(O)₂OH、-S(O)₂NH₂And the like.

The term "aryl" as used herein by itself or as part of another group refers to a monocyclic or bicyclic aromatic group containing 6 to 12 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl, which may themselves be substituted by one, two or three substituents independently and independently selected from the group consisting of halogen, nitro, ((C)₁-C₆) Alkyl) carbonyl, cyano, nitrile, hydroxy, trifluoromethyl, ((C)₁-C₆) Alkyl) -sulfonyl, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy and ((C)₁-C₆) Group of alkylsulfanyl (sulfanyl). As mentioned above, such "aryl" may be additionally substituted by one or several substituents.

The term "heteroaryl" as used herein refers to a group having 5 to 14 ring atoms; sharing 6, 10 or 14 pi (pi) electrons in a cyclic arrangement; and containing carbon atoms which may be substituted by halogen, nitro, (C)₁-C₆) Carbonyl, cyano, nitrile, trifluoromethyl, (C)₁-C₆) Sulfonyl group, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy or (C)₁-C₆) Sulfanyl substituted), and 1,2, 3, or 4 oxygen, nitrogen, or sulfur heteroatoms (where examples of heteroaryl groups are: thienyl, benzo [ b ]]Thienyl, naphtho [2, 3-b ]]Thienyl, thianthrenyl, furyl (furyl), furyl (furanyl), pyranyl, isobenzofuryl, benzoxazolyl, benzopyranyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, 4 aH-carbazolyl, carbolinyl, phenanthridinyl (phenonthridinyl), acridinyl, peridinyldiazophenyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl and phenoxazinyl.

Heteroaryl groups may be substituted with one, two or three substituents independently and independently selected from the group consisting of halogen, nitro, ((C)₁-C₆) Alkyl) carbonyl, cyano, nitrile, hydroxy, trifluoromethyl, ((C)₁-C₆) Alkyl) sulfonyl, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkenyl, (C)₁-C₆) Alkynyl, (C)₁-C₆) Alkoxy and (C)₁-C₆) Group of sulfanyl groups. As mentioned above, such "heteroaryl" may be additionally substituted by one or several substituents.

As used in the following description and claims of the present invention, the term "alkyl" by itself or as part of another group refers to a straight or branched chain alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl. Alkyl groups may also be substituted, e.g. by halogen atoms, hydroxy groups, C₁-C₄Alkoxy or C₆-C₁₂Aryl (which may also be substituted, for example by 1 to 3 halogen atoms). More preferably, the alkyl group is C₁-C₁₀Alkyl radical, C₁-C₆Alkyl or C₁-C₄An alkyl group.

As used in the following description and claims of the present invention, the terms "alkenyl" and "alkynyl" are defined similarly to alkyl, but contain at least one carbon-carbon double or triple bond, respectively.

As used in the following description and claims of the present invention, the term "alkoxy (alkoxy) (or alkoxy))" refers to an alkyl group attached by an oxygen atom, respectively, and the alkyl moiety is as defined above.

Substituent G, as defined above and as part of the substituents "alkyl", "alkenyl", "alkynyl" and "alkoxy", as used in the description and claims of the invention below³May be attached to any carbon of the corresponding substituents "alkyl", "alkenyl", "alkynyl" and "alkoxy". Thus, for example, the term "(G)³-(C₁-C₈) Alkoxy) aryl "does include the different possibilities associated with positional isomerism, such as (G)³-CH₂-CH₂-CH₂-CH₂-CH₂-CH₂-CH₂-CH₂-O-) aryl, (CH)₃-CH₂-CH₂-CH(G³)-CH₂-CH₂-CH₂-CH₂-O-) aryl and (CH (-CH)₂-CH₂-G³)(-CH₂-CH₃)-CH₂-CH₂-CH₂-O-) aryl, and the like.

Whenever the term "substituted" is used, it means that one or more hydrogens on the designated atom is replaced with a selection from the designated group using the expression "substituted" provided that the designated atom's normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e., a compound that is sufficiently robust to be isolated from a reaction mixture to a useful purity and formulated into a pharmaceutical composition. The substituents may be selected from halogen atoms (fluorine, chlorine, bromine, iodine), hydroxy groups, -SO₃H. Nitro group, ((C)₁-C₆) Alkyl) carbonyl, cyano, nitrile, trifluoromethyl, ((C)₁-C₆) Alkyl) sulfonyl, (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, (C)₁-C₆) Alkynyl, (C)₁-C₆) Alkoxy and (C)₁-C₆) A sulfanyl group.

In a second aspect, the invention provides for use as a medicament or pharmaceutical¹⁸F-labelled compounds of the formula I and compounds of the formula I¹⁹F standard reference compound.

The invention also relates to¹⁸F-labelled compounds of the formula I and compounds of the formula I¹⁹Use of an F standard reference compound in the manufacture of a medicament or pharmaceutical product for use in therapy.

In a more preferred embodiment, the use relates to the treatment of CNS diseases. CNS diseases include, but are not limited to, inflammatory and autoimmune diseases, allergic diseases, infectious diseases, toxin-induced and ischemia-induced diseases, pathophysiologically-related pharmacologic effects-induced inflammation, neurogenic inflammation, and neurodegenerative diseases.

More preferably, the CNS disease is selected from multiple sclerosis, alzheimer's disease, frontotemporal dementia, dementia associated with lewy bodies, leukoencephalopathy, epilepsy, neuropathic pain, amyotrophic lateral sclerosis, parkinson's disease, encephalopathy, brain tumors, depression, drug abuse, chronic inflammatory bowel disease, atheroma, atherosclerosis, arthritis, rheumatoid arthritis, pharmacologically induced inflammation, systemic inflammation of unclear origin.

In one embodiment, the disease is rheumatoid arthritis.

The invention also relates to a method of treating a central nervous system disorder as defined above, which comprises introducing into a patient a suitable amount of a compound of formula I, preferably¹⁸F-labelled compounds of formula I or of formula I¹⁹F standard reference compound.

In a third aspect, the present invention provides¹⁸A F-labelled compound of formula I as a diagnostic or imaging agent, preferably as an imaging agent for PET applications. It will be apparent to those skilled in the art that compounds of formula I and related derivatives of compounds of formula I such as L ═ iodine (e.g. I-123) are suitable as imaging agents for SPECT applications.

The invention also relates to¹⁸Use of a F-labelled compound of formula I for the preparation of an imaging agent.

In a more preferred embodiment, the use relates to imaging of CNS diseases. CNS diseases include, but are not limited to, inflammatory and autoimmune diseases, allergic diseases, infectious diseases, toxin-induced and ischemia-induced diseases, pathophysiologically-related pharmacologic effects-induced inflammation, neurogenic inflammation, and neurodegenerative diseases.

The invention also relates to imagingComprising introducing a detectable amount into a patient¹⁸An F-labelled compound of formula I and a step of imaging said patient.

It was found that the compound of formula I showed good initial brain absorption and good elimination at subsequent time points. The ratio of brain absorption of mice at 2min to 30min reflects this fact (percent absorption (% ID/g) of injected dose per 1 gram of tissue). The higher the ratio, the better the signal to background ratio. Thus, for example, compound 21 has a higher ratio of 4.85 compared to, for example, FEDAA (3) which exhibits a ratio of 2.00 and DPA-714(1.2) which exhibits a ratio of 2.43.

N-{2-[2-(¹⁸F) Fluoroethoxy group]-5-methoxybenzyl } -N- [2- (4-fluorophenoxy) py-rin-3-yl]Acetamide

In a fourth aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I, preferably¹⁸F-labelled compounds of formula I or of formula I¹⁹F standard reference compound; or pharmaceutically acceptable inorganic or organic acid salts, hydrates, complexes, esters, amides, solvates or prodrugs thereof. Preferably, the pharmaceutical composition comprises a physiologically acceptable carrier, diluent, adjuvant or excipient.

In a preferred embodiment, the pharmaceutical composition of the present invention comprises a compound of formula I which is a pharmaceutically acceptable salt, hydrate, complex, ester, amide, solvate or prodrug thereof.

As used in the following description and claims of the present invention, the terms "inorganic acid" and "organic acid" refer to inorganic acids including, but not limited to, acids such as carbonic acid, nitric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, perchloric acid or sulfuric acid or acid salts thereof such as potassium bisulfate; or suitable organic acids including, but not limited to, acids such as aliphatic acids, alicyclic acids, aromatic acids, araliphatic acids, heterocyclic acids, carboxylic acids and sulfonic acids, examples of which are formic acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, fumaric acid, pyruvic acid, benzoic acid, anthranilic acid, methanesulfonic acid (mesylic acid), fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, pamoic acid, methanesulfonic acid (methansulfonic acid), ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, 1,2, 2, 3, 3, 4, 4, 4-nonafluorobutane-1-sulfonic acid and sulfanilic acid, respectively.

In a fifth aspect, the present invention provides a pharmaceutical composition comprising¹⁸F labeled compound of formula I or pharmaceutically acceptable inorganic or organic acid salts, hydrates, complexes, esters, amides, solvates or prodrugs thereof.

Preferably, the pharmaceutical composition comprises a physiologically acceptable carrier, diluent, adjuvant or excipient.

The compounds of the present invention, preferably the radiolabeled compounds of formula I provided herein, in any pharmaceutically acceptable carrier, e.g., conventional media such as saline media or plasma media, may be administered intravenously as a pharmaceutical composition for intravenous injection. Such media may also contain conventional pharmaceutical materials such as pharmaceutically acceptable salts to adjust osmotic pressure, buffers, preservatives and the like. Among the preferred media are physiological saline solution and plasma.

Suitable pharmaceutically acceptable carriers are known to those skilled in the art. See, e.g., Remington's Practice of Pharmacy, 13th ed. and J.of.pharmaceutical Science & Technology, Vol.52, No.5, Sept-Oct, p.238-311, which references are incorporated herein by reference.

Compounds of formula I, preferably of the invention¹⁸Concentration of F-labelled compound and pharmaceutically acceptable carrier in e.g. aqueous medium, depending on the particular field of useDomain by domain. When satisfactory visualization of imaging targets, such as PBR (translocator, or inflammatory region or tumor), can be achieved, a sufficient amount of a compound of formula I is present in a pharmaceutically acceptable carrier.

The compounds of the invention, in particular the compounds of the invention, may be administered in any pharmaceutically acceptable carrier, for example a conventional medium such as a saline medium or a plasma medium¹⁸F radiolabelled Compounds, i.e. provided by the invention¹⁸The F-labelled compound of formula I is administered intravenously as a pharmaceutical composition for intravenous injection. Such a medium may also contain conventional pharmaceutical materials such as pharmaceutically acceptable salts for regulating osmotic pressure, buffers, preservatives and the like. Among the preferred media are physiological saline and plasma. Suitable pharmaceutically acceptable carriers are known to those skilled in the art. See, e.g., Remington's Practice of Pharmacy, 11th ed. and J&Technology，Vol.52，No.5，Sept-Oct.，p.238-311.x。

According to the invention, the radiolabeled compound of general formula I is administered as a neutral composition or as a salt with a pharmaceutically acceptable counterion in a single unit injectable dose. After radiolabelling according to the invention, injectable solutions can be prepared using any conventional carrier known to those skilled in the art, such as sterile saline solution or plasma, for diagnostic imaging of various organs, tumors, etc. Typically, the unit dose for administration of a diagnostic agent has a radioactivity of from about 0.1mCi to about 100mCi, preferably from 1mCi to 20 mCi. For radiotherapeutic agents, the radioactivity of the therapeutic unit dose is about 10mCi to 700mCi, preferably 50mCi to 400 mCi. The unit dose solution to be injected is from about 0.01ml to about 30 ml. For diagnostic purposes after intravenous administration, in vivo imaging of organs or diseases can be performed in about a few minutes. However, if desired, imaging may be performed hours or even longer after injection into the patient. In most cases, a sufficient dose will accumulate in the region to be imaged within about 0.1 hour, thereby enabling a scintigraphic image to be taken. Any conventional method of scintigraphic imaging for diagnostic purposes may be used in accordance with the present invention.

As used in the following description and claims of the invention, the term "prodrug" denotes any covalently bonded compound that releases the active parent drug of formula I, preferably¹⁸F-labelled compounds of formula I.

The term "prodrug" as used herein denotes pharmaceutically acceptable derivatives such as esters, amides and phosphates, such that the in vivo biotransformation product of the derivative is the active drug as defined for the compound of formula (I). The literature on prodrugs is incorporated herein by Goodman and Gilman (The pharmaceutical-local Basis of Therapeutics, 8 ed, McGraw-HiM, int. Ed.1992, "biological of Drugs", p 13-15). Prodrugs of the compounds of the present invention are prepared by modifying the functional groups present in the compounds in such a way that: the modification is either a routine procedure or cleavage of the parent compound in vivo. Prodrugs of the compounds of the present invention include those compounds in which, for example, a hydroxyl or amino group on an asymmetric carbon atom is bonded to any group that, when the prodrug is administered to a patient, cleaves to form a free hydroxyl or free amino group, respectively.

Typical examples of prodrugs are described in, for example, WO 99/33795, WO 99/33815, WO 99/33793 and WO 99/33792, which are all incorporated herein by reference.

Prodrugs are characterized by excellent water solubility, enhanced bioavailability, and are readily metabolized in vivo into active inhibitors.

As will be apparent to those skilled in the art, wherein L is R³The radiofluorination reaction of compounds of formula I may result in by-products and compounds other than those shown in formula I. These products are characterized, for example, by L being hydroxy or-N (Me)₂(optionally in conjunction with a nucleophilic aromatic substitution (substention) reaction); or for example L is a hydroxyl group, such as dimerization of the precursor compound to an ether, or elimination of a leaving group to produce the corresponding alkene (optionally along with an aliphatic nucleophilic substitution reaction). Such thatBy-products and similar derivatives are typically isolated from the reaction mixture, but may still be present in some amount in part in the radiopharmaceutical composition to be administered to a patient or mammal.

In a sixth aspect, the invention relates to a compound of formula I, wherein L is [ [ solution ] ]¹⁹F]Fluorine, preferably L is [2 ]¹⁹F]Fluorine compounds of formula I are:

N- [2- (2-fluoroethoxy) -5-methoxybenzyl ] -N- [2- (4-methoxyphenoxy) pyridin-3-yl ] acetamide

N- {2- [3- (fluoropropoxy ] -5-methoxybenzyl } -N- [2- (4-fluorophenoxy) pyridin-3-yl ] acetamide

N- {2- [3- (fluoropropoxy ] -5-methoxybenzyl } -N- [2- (4-iodophenoxy) pyridin-3-yl ] acetamide

N- [2- (3-Fluoropropoxy) -5-methoxybenzyl ] -N- [2- (phenoxy) pyridin-3-yl ] acetamide

N- [2- (3-Fluoropropoxy) -5-methoxybenzyl ] -N- [2- (2-fluorophenoxy) pyridin-3-yl ] acetamide

N- [2- (4-chlorophenoxy) pyridin-3-yl ] -N- [2- (3-fluoropropoxy) -5-methoxybenzyl ] acetamide

N- [2- (3-Fluoropropoxy) -5-methoxybenzyl ] -N- [2- (4-methoxyphenoxy) pyridin-3-yl ] acetamide

N- {2- [ fluoromethoxy ] -5-methoxybenzyl } -N- [2- (4-fluorophenoxy) pyridin-3-yl ] acetamide

N- {2- [ fluoromethoxy ] -5-methoxybenzyl } -N- [2- (4-iodophenoxy) pyridin-3-yl ] acetamide

N- [2- (fluoromethoxy) -5-methoxybenzyl ] -N- [2- (phenoxy) pyridin-3-yl ] acetamide

N- [2- (fluoromethoxy) -5-methoxybenzyl ] -N- [2- (2-fluorophenoxy) pyridin-3-yl ] acetamide

N- [2- (4-chlorophenoxy) pyridin-3-yl ] -N- [2- (fluoromethoxy) -5-methoxybenzyl ] acetamide

N- [2- (fluoromethoxy) -5-methoxybenzyl ] -N- [2- (4-methoxyphenoxy) pyridin-3-yl ] acetamide

If chiral centers or other forms of isomeric centers are present in the compounds of the present invention, the present invention is intended to encompass all forms of such stereoisomers, including enantiomers and diastereomers. Compounds containing chiral centers can be used as racemic mixtures or enantiomerically enriched mixtures, or racemic mixtures can be separated using well-known techniques and the individual enantiomers can be used separately. In the case where the compound has an unsaturated carbon-carbon double bond, (Z) -isomer and (E) -isomer are within the scope of the present invention. Where a compound may exist in tautomeric forms such as keto-enol tautomers, the invention includes each tautomeric form whether it exists in equilibrium or predominantly in one form.

When referring to the compounds of the formula of the present invention as such and any pharmaceutical compositions thereof, the present invention includes all hydrates, salts, solvates, complexes and prodrugs of the compounds of the present invention, unless otherwise indicated. A prodrug is any covalently bonded compound that releases the active parent drug of formula I.

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

In a seventh aspect, the present invention relates to compounds of formula IV, including all isomeric forms of said compounds, including but not limited to enantiomers and diastereomers and racemic mixtures, and any pharmaceutically acceptable salts, esters, amides, complexes, or prodrugs thereof,

wherein

R¹⁰Is selected from the group consisting of₁-C₆) The group of alkyl groups and hydrogen;

R¹⁶selected from the group consisting of hydrogen, halogen, trifluoromethyl, (C)₁-C₅) Alkyl, (C)₂-C₅) Alkynyl group), (C)₂-C₅) Alkenyl and (C)₁-C₅) A group of alkoxy groups;

A³and A⁴Are the same or different and have the structure (R)¹²)(R⁴)(R⁵) A phenyl group;

R¹²selected from the group consisting of R¹³And hydrogen;

R¹³is a hydroxyl group, and the hydroxyl group,

with the proviso that the compound of formula VI contains exactly one R¹³；

At each occurrence, R⁴And R⁵Independently and independently selected from the group consisting of hydrogen, halogen, trifluoromethyl, (C)₁-C₅) Alkyl, (C)₂-C₅) Alkynyl group), (C)₂-C₅) Alkenyl and (C)₁-C₅) A group of alkoxy groups;

in a preferred embodiment, R¹⁶Selected from the group comprising hydrogen, fluoro, chloro, iodo, methyl, methoxy and trifluoromethyl;

in a more preferred embodiment, R¹⁶Selected from the group consisting of hydrogen, fluorine, chlorine, iodineAnd methyl;

in an even more preferred embodiment, R¹⁶Selected from the group comprising hydrogen and chlorine;

in a most preferred embodiment, R¹⁶Is hydrogen;

in a more preferred embodiment, R, at each occurrence⁴And R⁵Independently and each selected from the group comprising hydrogen, fluoro, methyl and methoxy;

in a preferred embodiment, R¹⁰Selected from the group comprising methyl and hydrogen;

with the proviso that the compound of formula VI contains exactly one R¹²。

In an eighth aspect, the present invention relates to a method for obtaining a compound of formula I, wherein L is [ [ solution ], [ solution ] ]¹⁸F]Fluorine or [ alpha ], [ alpha¹⁹F]Fluorine.

Surprisingly, both methods have been identified for obtaining such compounds.

In a first embodiment, a precursor compound of formula I, wherein L is R as defined above, is reacted with a F-fluorinating agent³。

Preferably, the F-fluorinating agent is a compound comprising an F-anion, preferably a compound selected from the group consisting of 4, 7, 13, 16, 21, 24-hexaoxa-1, 10-diazabicyclo [8.8.8]-hexacosane KF, i.e. the crown ether salt Kryptofix KF; KF; HF; KHF₂(ii) a CsF; NaF and tetraalkylammonium salts of F, e.g. N (butyl)₄F (tetrabutylammonium fluoride); and wherein F ═¹⁸F or¹⁹F。

More specifically, for¹⁸F-labelled Compounds of formula I, for obtaining¹⁸F-labelled formulaA first embodiment of a method for radiolabeling a compound of formula I comprises the steps of:

-subjecting a compound of formula I having a suitable leaving group to a fluorinating agent¹⁸F is radiolabeled to obtain¹⁸F-labelled compounds of formula I.

The term "radiolabeled" molecule as used herein generally means that the molecule will be labeled¹⁸F-atoms are introduced into the molecule.

The fluorinating agent is as defined above, wherein F ═¹⁸F。

In a second embodiment, L is [2 ]¹⁸F]Fluorine or [ alpha ], [ alpha¹⁹F]The synthesis of the fluoro compound of formula I comprises the steps of:

-fluorinating the compound of formula V with a F-fluorinating agent F-to yield the compound of formula IV,

formula V

Formula IV

-substituting said compound of formula IV with a compound of formula VI,

formula VI

Wherein F in the formula IV is [ [ alpha ] ]¹⁸F]Fluorine or [ alpha ], [ alpha¹⁹F]The fluorine is introduced into the reaction mixture containing the fluorine,

a is an integer of 0 to 5, preferably 0 to 2, more preferably 0 to 1;

b is a leaving group, preferably halogen, in particular chlorine, bromine, iodine, mesyloxy, tosyloxy, trifluoromethylsulfonyloxy, nona-fluorobutylsulfonyloxy, (4-bromo-phenyl) sulfonyloxy, (4-nitro-phenyl) sulfonyloxy, (2-nitro-phenyl) sulfonyloxy, (4-isopropyl-phenyl) sulfonyloxy, (2, 4, 6-tri-isopropyl-phenyl) sulfonyloxy, (2, 4, 6-trimethyl-phenyl) sulfonyloxy, (4-tert-butyl-phenyl) sulfonyloxy and (4-methoxy-phenyl) sulfonyloxy;

R¹²selected from the group consisting of R¹³And hydrogen;

R¹³is a hydroxyl group, and the hydroxyl group,

with the proviso that the compound of formula VI contains exactly one R¹³；

in a more preferred embodiment, at each occurrenceWhen R is⁴And R⁵Independently and each selected from the group comprising hydrogen, fluoro, methyl and methoxy;

in a preferred embodiment, R¹⁰Selected from the group comprising hydrogen and methyl;

in a more preferred embodiment, R¹⁶Selected from the group comprising hydrogen, fluorine, chlorine, iodine and methyl;

in a most preferred embodiment, R¹⁶Is hydrogen;

wherein the F-fluorinating agent is as defined above,

and wherein F ═¹⁸F or¹⁹F，

With the proviso that the compound of formula VI contains exactly one R¹²。

Preferably, B is selected from the group comprising iodo, bromo, chloro, mesyloxy, tosyloxy, trifluormethylsulfonyloxy and nona-fluorobutylsulfonyloxy.

More preferably for obtaining¹⁸A second embodiment of the method for radiolabeling a F-labeled compound of formula I comprises the steps of:

by fluorinating agents¹⁸F radiolabelling a compound of formula V to give a compound of formula IV, and

-substituting a compound of formula IV with a compound of formula VI.

¹⁸F-labelled compounds of the formula IV

Or pharmaceutically acceptable inorganic or organic acid salts, hydrates, complexes, esters, amides, solvates or prodrugs thereof,

wherein

B is a leaving group;

leaving group B is a leaving group known or apparent to those skilled in the art and derived from, but not limited to, those described or named in the following references: synthesis (1982), p.85-125, Table 2 (p.86; (the last item of Table 2 should be modified to: "n-C₄F₉S(O)₂-O-nonaflatat "instead of" n-C₄H₉S(O)₂-O-nonaflat "), Carey and Sundberg, Organische Synthesis, (1995), page 279-281, table 5.8; or Netscher, Recent res.dev.org.chem., 2003, 7, 71-83, scheme 1,2, 10 and 15;

in a more preferred embodiment, B is selected from the group comprising:

a) the amount of iodine is such that,

b) the bromine is added to the reaction mixture,

c) the chlorine is added to the reaction mixture in the presence of chlorine,

d) a mesyloxy group, which is a group having a sulfonyl group,

e) a tosyloxy group,

f) a trifluoromethylsulfonyloxy group, and

g) nonafluorobutylsulfonyloxy;

a is an integer of 0 to 4, preferably a is an integer of 0 to 2, and more preferably a is an integer of 0 to 1;

the compound of formula V is

wherein

B is as defined above for the compound of formula IV, and

a is as defined above for the compound of formula IV,

the fluorinating agent is as defined above.

In a preferred embodiment, the fluorinating agent is a fluorine radioisotope derivative.

More preferably, the fluoro radioisotope derivative is¹⁸And F derivative. More preferably still, the first and second liquid crystal compositions are,¹⁸the F derivative is 4, 7, 13, 16, 21, 24-hexaoxa-1, 10-diazabicyclo [8.8.8]-hexacosane K¹⁸F (crown ether salt Kryptofix K)¹⁸F)、K¹⁸F、H¹⁸F、KH¹⁸F₂、Cs¹⁸F、Na¹⁸F or¹⁸Tetraalkylammonium salts of F (e.g. [ F-18]]Tetrabutylammonium fluoride). More preferably, the fluorinating agent is K¹⁸F、H¹⁸F or KH¹⁸F₂Most preferably K¹⁸F(¹⁸F fluoride anion).

The radiofluorination reaction may be carried out, for example, in conventional reaction vessels (e.g., Wheaton vials) or microreactors known to those skilled in the art. The reaction can be heated by conventional means such as an oil bath, heating block or microwaves. The radiofluorination reaction was carried out in dimethylformamide with potassium carbonate as base and "kryptofix" as crown ether. But other solvents known to those skilled in the art may also be used. These possible conditions include, but are not limited to: dimethylsulfoxide and acetonitrile were used as solvents and tetraalkylammonium carbonate and tetraalkylphosphonium carbonate as bases. Water and/or alcohol may participate in this reaction as a co-solvent. The radiofluorination reaction is carried out for 1 to 60 minutes. The preferred reaction time is 5 to 50 minutes. More preferably the reaction time is from 10 to 40 minutes. These and other conditions for such radiofluorination are known to those skilled in The art (Coenen, Fluorine-18 laboratory Methods: Features and Possibilities of Basic Reactions, (2006), in: Schubiger P.A., Friebe M., Lehmann L., (eds), PET-Chemistry-The driving force in Molecular imaging. Springer, Berlin Heidelberg, pp.15-50). Radiofluorination can be carried out in "hot chambers" and/or by using Modules (reviewed in Krasikowa, Synthesis Modules and Automation in F-18 labeling (2006), in: Schubiger P.A., Friebe M., Lehmann L., (eds), PET-Chemistry-The Driving Force in molecular imaging. Springer, Berlin Heidelberg, pp.289-316), which allow automated or semi-automated Synthesis.

Furthermore, the present invention provides compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier or diluent.

In one embodiment, the compound is¹⁸F labeled compound.

In another embodiment, the compound is¹⁹F labeled compound.

In yet another embodiment, the compound is a precursor compound.

The invention also provides compounds of the invention, preferably¹⁸F-or¹⁹F-labeled compounds of the invention; or a composition of the invention for use as a medicament or diagnostic agent or imaging agent.

The invention also provides compounds of the invention, preferably¹⁸F-or¹⁹Use of an F-labelled compound of the invention, or a composition of the invention, in the manufacture of a medicament for the treatment and/or diagnosis and/or imaging of a Central Nervous System (CNS) disease.

The invention also provides for the use as diagnostic or imaging agents, particularly for diseases of the central nervous system¹⁸F-labelled Compounds of formula IOr compositions comprising such compounds.

The invention also provides a kit comprising a sealed vial containing a predetermined amount of a compound,

a) which is a precursor compound of formula I, or

b) A compound of formula V and a compound of formula VI as defined above.

The present invention also provides a method for detecting the presence of a PBR receptor (translocator) in a patient, preferably for imaging a central nervous system disorder in a patient, the method comprising:

introducing a detectable quantity into the patient¹⁸F-labelled compounds of the invention or compositions comprising such compounds,

and detecting the compound or the composition by Positron Emission Tomography (PET).

The present invention also provides a method for treating a central nervous system disorder, the method comprising the steps of: introducing an appropriate amount of a compound of the invention, preferably¹⁸F-or¹⁹F-labelled compounds of the invention.

A general synthesis scheme for a tricyclic framework comprising aromatic ring systems A, B and C is shown in scheme 1: thus, compounds of the E1 class are alkylated by phenol anions in the direction of compounds of the E2 class, whereas "(N)" represents a nitrogen-containing substituent, preferably a nitro group, and "(X)" represents a leaving group, such as halogen. The substituent "(N)" is converted to the aniline derivative E3 by methods known to those skilled in the art (e.g., if "(N)" is nitro, hydrogenation results in the desired compound E3). Reductive amination reactions with aldehydes of the E8 class yield anilines of the E4 class.

Scheme 1

Compounds of the E3 class may also be converted to E5 compounds by amidation or N-acetylation reactions known to those skilled in the art. Compounds of class E4 can be converted to amides of class E6. Alkylation of compounds of the E5 class with alkylating agents of the E9 class, representing "C-rings", also produces compounds of the E6 class. There are two ways to introduce the F-18 tag (and optionally the corresponding F-19 tag). For example, the introduction of a suitable leaving group (immobilization) can be accomplished by mesylation of the corresponding alcohol (compare scheme 2 (9) → (10)). However, alkylation of small F-18-labeled building blocks (prosthetic groups, E10) can also be used to attach them to nucleophilic functional groups incorporated into compounds of the E6 class (compare scheme 3: (15) → (19)).

Scheme 2 describes a specific example of a method for synthesizing a compound of formula I:

scheme 2

Aniline 6(j.med. chem. (2002), 45, 23, 5182-5185) and aldehyde 7(EP1894915a1) were converted in a reductive amination reaction using sodium tris (acetoxy) borohydride. Subsequent acetylation of the crude secondary aniline yields the desired product 8. The tetrahydropyranyl ether 8 was cleaved under acidic conditions using PPTS in methanol. The desired alcohol 9 was converted to the corresponding mesylate 10 using methanesulfonyl chloride and triethyl and Hunig's base in dichloromethane. Subsequent fluorination reactions with KF and kryptofix yielded the desired [ F-18] labeled compound 11. The radiofluorination reaction may be carried out in a conventional reaction vessel (e.g. a wheatstone vial) or a microreactor, for example, as known to those skilled in the art. The reaction can be heated by conventional means such as an oil bath, heating block or microwaves. The radiofluorination reaction was carried out in dimethylformamide with potassium carbonate as base and "kryptofix" as crown ether. But other solvents known to those skilled in the art may also be used. These possible conditions include, but are not limited to: dimethylsulfoxide and acetonitrile were used as solvents and tetraalkylammonium carbonate and tetraalkylphosphonium carbonate as bases. Water and/or alcohol may participate in this reaction as a co-solvent. The radiofluorination reaction is carried out for 1 to 60 minutes. The preferred reaction time is 5 to 50 minutes. More preferably the reaction time is from 10 to 40 minutes. These and other conditions for such radiofluorination are known to those skilled in the art (Coenen, Fluorine-18 laboratory Methods: Features and challenges of Basic Reactions, (2006), in: Schubiger P.A., Friebe M., Lehmann L., (eds), PET-Chemistry-the driving Force in Molecular imaging. Springer, Berlin Heidelberg, pp.15-50). Radiofluorination can be carried out in "hot chambers" and/or by using Modules (reviewed in Krasikowa, Synthesis Modules and Automation in F-18 labeling (2006), in: Schubiger P.A., Friebe M., Lehmann L., (eds), PET-Chemistry-The Driving Force in molecular imaging. Springer, Berlin Heidelberg, pp.289-316), which allow automated or semi-automated Synthesis.

Another exemplary method is shown in scheme 3: aniline 12(ABCR) was reacted with aldehyde 13 by reductive amination using sodium tris (acetoxy) borohydride (bioorg. med. chem. lett. (2007), 2614-2617). Subsequent acetylation of the crude product yields the desired product 14. Benzyl ether 14 is cleaved by methods known to those skilled in the art. Typically, heterogeneous catalytic hydrogenation using hydrogen and palladium on charcoal is used to obtain phenol 15. Phenol 15 can alternatively be used [ [ alpha ] ]¹⁸F]The fluorobromoethane (generated from 2-bromoethyl triflate) (bioorg. Med. chem.; 11; 12; 2003; 2519-2528)) is alkylated to obtain compound 19. Compound 15 was alkylated with 2-benzyloxybromoethane in acetonitrile using sodium carbonate as the base to give compound 16. Compound 15 may also be alkylated with 1-fluoro-2-iodoethane or with 1-bromo-2-fluoroethane. The product of this conversion was the corresponding F-19 reference standard 20 for the radiofluorination experiment using mesylate 18. Mesylate 18 may be prepared from alcohol 17 using methanesulfonyl chloride and triethylamine in dichloromethane. Benzyl groups on palladium on carbon by hydrogen in isopropanolEther 16 is hydrogenated to produce alcohol 17 as previously described.

Scheme 3

Similar compounds that can be produced by the method are:

N-{2-[2-[¹⁸F]fluoroethoxy group]Benzyl } -N- [2- (2-fluorophenoxy) pyridin-3-yl]Acetamide

N- [2- (2, 6-Difluorophenoxy) pyridin-3-yl]-N-[2-(3-[¹⁸F]Fluoropropoxy) benzyl]Acetamide

N- [2- (2-fluoro-3-methylphenoxy) pyridin-3-yl]-N-{5-[3-[¹⁸F]Fluoropropyl) -2-methoxybenzyl } acetamide

N-{5-[2-[¹⁸F]Fluoroethoxy group]-2-methoxybenzyl } -N- [2- (4-methylphenoxy) pyridin-3-yl]Acetamide

N-(2-{4-[2-[¹⁸F]Fluoroethoxy group]Phenoxy } pyridin-3-yl) -N- (2-methoxybenzyl) propanamide

N- [2- (2, 3-dimethylphenoxy) pyridin-3-yl]-N-{2-[2-[¹⁸F]Fluoroethoxy group]-5-methoxybenzyl } propanamide

Scheme 4 represents another method of synthesizing compounds of formula I:

scheme 4

Compound 22 (scheme 4) is generated from 3-nitro-2-phenoxypyridine by oxidation with tert-butyl hydroperoxide (e.g., Journal of Medicinal Chemistry; English; 50; 1; 2007; 2-5). Bromination of alcohol 22 is carried out towards compound 23 using phosphorus tribromide (e.g., Tetrahedron Letters; English; 32; 34; 1991; 4263-. The reduction of the nitro group of compound 23 is carried out with iron powder in acid (e.g.Recueil des Travaux Chimizes des Pays-Bas; 64; 1945; 102, 104).

Reductive amination of 2-methoxybenzaldehyde with aniline 24 (e.g. Journal of organic chemistry (2004), 69, 35) produces an amine 25 which can be acetylated in the direction of the amide 26. Radiolabeling bromopyridine 26 with F-18 potassium fluoride yields the desired compound F-18 labeled 27. Methods for radiolabelling fluoropyridines are known to those skilled in The art (Dolle et al, (2006), in: Schubiger P.A., Friebe M., Lehmann L., (eds), PET-Chemistry-The Driving Force in molecular imaging, Springer, Berlin Heidelberg).

Nonradioactive fluorination of compound 26 with potassium fluoride or tetrabutylammonium reagent yields the corresponding F-19 reference compound.

The compounds of the invention may be used in methods of imaging, diagnosing, and treating central nervous system disorders and neurodegenerative disorders. The preferred imaging method is PET. The central nervous system or neurodegenerative disorder can be, but is not limited to, alzheimer's disease, dementia, multiple sclerosis, or amyotrophic lateral sclerosis.

Drawings

FIG. 1: shows a scheme for synthesizing the compounds of the present invention.

FIG. 1.1: [¹⁸F]2d i.v. is injected into a normal mouse, blood and brain¹⁸F]Absorption and elimination of radioactivity over time (n-3 at each time point).

FIG. 1.2: [¹⁸F](ii) blood and brain of a normal mouse after injection of-5 d i.v.)¹⁸F]Absorption and elimination of radioactivity over time (n-3 at each time point).

FIG. 2: the ratio of 2min to 30min of compound 21 brain uptake (percent uptake of injected dose per 1 gram of tissue (% ID/g)) in mice compared to FEDAA (3) and DPA-714. The higher the ratio, the better the signal to background ratio.

FIG. 2.1: [¹⁸F]Ex vivo autoradiography of transversal sections of rat brain 30min after-2 d (A-C) injection, of kainic acid treated rat model and of respective sham controls. Activated microglia on the same sections were visualized by subsequent immunohistochemistry using Ox-42 antibody (D-I). The kainic acid treated rats (a) were compared to sham treated rats (C). Note the strong signal of the hippocampus, which is known to be affected in this model. In a rat treated with kainic acid, co-injection of [2 ]¹⁹F]-2e blocks these signals (B).

The horizontal lines represent 1000 μm (D, F, H) and 100 μm (E, G, I). The sections were placed at the-3.1 mm bregma. The regions of interest for quantification and calculation of the respective hippocampal/cerebellar ratios are marked with dashed circles.

FIG. 2.2: [¹⁸F]Ex vivo autoradiography of brain cross sections of kainic acid treated rats and of rats of each sham control 30min after-5 d (A-C) injection. Activated microglia on the same sections were visualized by subsequent immunohistochemistry using Ox-42 antibody (D-I). The kainic acid treated rats (a) were compared to sham treated rats (C). Note the strong signal of the hippocampus, which is known to be affected in this model. In a rat treated with kainic acid, co-injection of [2 ]¹⁹F]-5e blocks these signals (B).

FIG. 3: signal to background ratio calculated from quantitative ex vivo autoradiographic signals of brain sections of kainic acid-treated rats, expressed as hippocampal/cerebellar ratio.

Experimental part

The general steps are as follows:

a: fluorination with non-radioactive [ F-19] fluorides

To a 1eq solution of the starting material in acetonitrile (2ml/eq.) was added 1.1eq potassium fluoride and kryptofix (1.1 eq.). The reaction mixture was heated with a microwave (130 ℃, 15min) and cooled again to room temperature. The reaction mixture was diluted with 10ml diethyl ether and 10ml water. The organic phase was separated. The aqueous phase was extracted three times with 10ml of diethyl ether. The combined organic phases were washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography with an ethyl acetate-hexane gradient.

B: fluorination with radioactive [ F-18] fluorides

Mixing the water solution¹⁸F]Fluoride (0.1-5GBq) was collected (trap) on QMA cartridges (cartridge) and 1mg K in 5mg K2.2.2+ 50. mu.l water in 0.95ml MeCN₂CO₃Elute into wheaton vial (5 ml). The solvent was removed by heating at 120 ℃ for 10min under a stream of nitrogen. Anhydrous MeCN (1ml) was added and evaporated as above. This step was repeated three times. A solution of the starting material (1mg) in 300. mu.l anhydrous DMF was added. After heating at 120 ℃ for 10min, the crude reaction mixture was analyzed by analytical HPLC: ACE3-C1850mm x 4.6 mm; solvent gradient: starting 5% acetonitrile in water-95% acetonitrile in water, 7 minutes, flow rate: 2 ml/min. The desired F-18 labeled product was confirmed by co-injection of the corresponding nonradioactive F-19 fluorine standard in analytical HPLC. The crude product was pre-purified via C18SPE cartridge and the pre-purified product (50-2500MBq) was purified by preparative HPLC: ACE 5-C18-HL 250mm x 10 mm; 62% isocratic acetonitrile in water, 25min, flow rate: 3 ml/min. The desired product obtained (30-2000MBq) was reconfirmed by co-injection of non-radioactive F-19 fluorine standards in analytical HPLC. The samples were diluted with 60ml water and fixed on a Chromafix C18(S) cartridge, which was washed with 5ml water and eluted with 1ml ethanol to obtain 20-1800MBq in 1000 μ l EtOH.

H: alkylation of phenols

To a stirred solution of 1eq of the starting material (phenol derivative) and 1.5eq of potassium carbonate in dimethylformamide 3ml/l eq is added 2.5mmol of alkylating agent. The reaction mixture was heated at 70 ℃ for 6 hours, or by microwave heating to 110 ℃ for 15 min. The solvent of the reaction mixture was evaporated. Water and methyl tert-butyl ether were added. The organic phase was separated. The aqueous phase was extracted three times with methyl tert-butyl ether diethyl ether. The combined organic phases were washed with water, brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography with an ethyl acetate-hexane gradient.

I: conversion of alcohols to the corresponding O-sulfonates

To a solution of 1eq. starting material and 1.5eq. diisopropylethylamine in 3ml/mmol dichloromethane was added dropwise a small amount of 1.3eq. methanesulfonyl chloride in dichloromethane at-10 ℃. The stirred reaction mixture was warmed to room temperature over 4.5h and diluted with dichloromethane. The organic phase was washed with saturated sodium bicarbonate solution, water and brine. The organic phase was dried over magnesium sulfate. The crude product was purified by column chromatography over silica gel (ethyl acetate-hexane gradient).

K: conversion of alcohols to the corresponding O-sulfonates (scheme 2)

Arylsulfonyl chloride (1.1eq.) (1ml/eq.) in dichloromethane was added dropwise to a solution of 1eq. starting material in dichloromethane (1.4ml/eq.) and pyridine (1.4ml/eq.) at-10 ℃. The stirred reaction mixture was warmed to room temperature over 4.5h and diluted with dichloromethane. The organic phase was washed with 0.25N sulfuric acid (three times), saturated sodium bicarbonate solution, water and brine. The organic phase was dried over magnesium sulfate. The crude product was purified by column chromatography over silica gel (ethyl acetate-hexane gradient).

L (1): heterogeneous hydrogenation

To a stirred solution of about 20-50mg palladium on carbon (10%) in isopropanol (8ml/l mmol of starting material) was added a small amount of benzyl ether in isopropanol (educt). The reaction mixture was stirred under a hydrogen atmosphere for 16-20 hours. Filtering the reaction mixture; and the solvent was evaporated. The residue was purified by column chromatography with an ethyl acetate-hexane gradient.

L (2): hydrogenation with iron

To a stirred solution of 1eq. starting material (nitro derivative) and 5eq. iron powder in ethanol (about 86eq.) was added 1ml/eq.hcl (37% aqueous solution). The solution was refluxed for 1 hour. The solution was cooled to 0 ℃. 1N NaOH (40ml/mmol of starting material) was added dropwise. Dichloromethane and brine were added. The organic phase was separated. The aqueous solution was extracted twice with dichloromethane (rice). The combined organic phases were washed with brine and dried over magnesium sulfate. The solvent was evaporated. The residue was purified by column chromatography with an ethyl acetate-hexane gradient.

W: reductive amination and subsequent acetylation

A stirred solution of aldehyde (1eq.) and amine (1eq.) in 60ml of dichloroethane (pH 5) was adjusted to pH 5 with glacial acetic acid. To the solution was added 70mmol of sodium triacetoxyborohydride. The reaction mixture was stirred overnight and diluted with 5ml of water. The pH was adjusted to 8-9 with aqueous sodium hydroxide. The mixture was extracted three times with dichloromethane. The combined organic phases were washed with water and brine and dried over magnesium sulfate. The desired crude product was obtained after evaporation. The crude product was diluted in anhydrous pyridine (1.3ml/mmol starting material) and cooled to 0 ℃. To this stirred solution was added dropwise 1.25eq. The reaction mixture was stirred overnight, reduced to one third of its volume and diluted with dichloromethane (2ml/mmol) and water (2 ml/mmol). The aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography with an ethyl acetate-hexane gradient.

Z: deprotection of THP ethers

0.15eq.PPTS was added to a solution of 1 eq.tetrahydropyran ether in 7ml/mmol methanol. The reaction mixture was stirred overnight and poured into a stirred solution of ice water and tert-butyl methyl ether. The organic phase was separated. The aqueous phase was extracted three times with tert-butyl methyl ether. The combined organic phases were washed with diluted sodium bicarbonate, brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography with an ethyl acetate-hexane gradient.

Example 1

a) Synthesis of N- {2- [2- (benzyloxy) ethoxy ] -5-methoxybenzyl } -N- [2- (4-fluorophenoxy) pyridin-3-yl ] acetamide (1a)

4.1g (20mmol)2- (4-fluorophenoxy) pyridin-3-amine (Helv. Chim. acta; 48; 1965; 336-347) and 5.7g (20mmol)2- [2- (benzyloxy) ethoxy ] -5-methoxybenzaldehyde (EP1894915A1) were converted according to general procedure W. The desired product was obtained in quantitative yield.

MS-ESI：517(M⁺+1，100)。

Elemental analysis:

calculated values: c69.75% H5.66% N5.42%

Measured value: c69.72% H5.67% N5.40%

b) Synthesis of N- [2- (4-fluorophenoxy) pyridin-3-yl ] -N- [2- (2-hydroxyethoxy) -5-methoxybenzyl ] acetamide (1b)

According to general procedure "L", the desired product 1b was obtained from 1a (1.67g, 3.23mmol) in 83% yield (1.15 g).

MS-ESI：427(M⁺+1，100)。

Elemental analysis:

calculated values: c64.78% H5.44% N6.57%

Measured value: c64.75% H5.45% N6.56%

c) Synthesis of 2- [2- ({ acetyl [2- (4-fluorophenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] ethyl methanesulfonate (1c)

According to general procedure "I", the desired product 1c was obtained from 1b (300mg, 0.7mmol) in 97% yield (350 mg).

MS-ESI：505(M⁺+1，100)。

Elemental analysis:

calculated values: c57.13% H4.99% N5.55%

Measured value: c57.14% H5.00% N5.56%

d)N-[2-(2-[¹⁸F]Fluoroethoxy) -5-methoxybenzyl]-N- [2- (4-fluorophenoxy) pyridin-3-yl]Synthesis of acetamide (1d)

According to general step "B", the desired product (1d) is obtained from (1 c).

e) Synthesis of 2- (2-fluoroethoxy) -5-methoxybenzaldehyde (1e)

According to general procedure "H", the desired product 1e was obtained from 100mmol of 2-hydroxy-5-methoxybenzaldehyde (Aldrich) and 250mmol of 1-bromo-2-fluoroethane (Aldrich) in 82% yield (82 mmol).

MS-ESI：199(M⁺+1，100)。(Aldrich)。

Elemental analysis:

calculated values: c60.60% H5.59%

Measured value: c60.61% H5.59%

f) Synthesis of N- [2- (2-fluoroethoxy) -5-methoxybenzyl ] -N- [2- (4-fluorophenoxy) pyridin-3-yl ] acetamide (1f) (reference standard)

According to general procedure "W", the expected product 1f was obtained from 1.51mmol (309mg) of 2- (4-fluorophenoxy) pyridin-3-amine (Helv. Chim. acta; 48; 1965; 336- & 347) and 1.51mmol (300mg) of 1e in 88.2% (572mg) yield.

MS-ESI：429(M⁺+1，100)。(Aldrich)。

Elemental analysis:

calculated values: c64.48% H5.18% N6.54%

Measured value: c64.46% H5.19% N6.54%

Example 2

a) Synthesis of N- [2- (4-methoxyphenoxy) pyridin-3-yl ] -N- { 5-methoxy-2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy ] benzyl } acetamide (2a)

According to general procedure "W", the desired product 2a was obtained in 55% yield from 463mg of 5-methoxy-2- [2- (tetrahydro-2H-pyran-2-oxy) ethoxy ] benzaldehyde (EP1894915A1) and 340mg of 2- (4-methoxyphenoxy) pyridin-3-amine (J.Org.Chem.; 60; 16; 1995; 4991-.

MS-ESI：523(M⁺+1，100)。

Elemental analysis:

calculated values: c66.65% H6.56% N5.36%

Measured value: c66.63% H6.57% N5.35%

b) Synthesis of N- [2- (2-hydroxyethoxy) -5-methoxybenzyl ] -N- [2- (4-methoxyphenoxy) pyridin-3-yl ] acetamide (2b)

The expected product 2b was obtained from 2a (432mg, 0.83mmol) in 73% yield (265mg) according to general procedure "Z".

MS-ESI：439(M⁺+1，100)。

Elemental analysis:

calculated values: c65.74% H5.98% N6.39%

Measured value: c65.73% H5.97% N6.39%

c) Synthesis of 2- [2- ({ acetyl [2- (4-methoxyphenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] ethyl methanesulfonate (2c)

The desired product 2c was obtained from 2b (256mg, 0.58mmol) in 96% yield (289mg) according to general procedure "I".

MS-ESI：517(M⁺+1，100)。

Elemental analysis:

calculated values: c58.13% H5.46% N5.42%

Measured value: c58.16% H5.47% N5.41%

d)N-[2-(2-[¹⁸F]Fluoroethoxy) -5-methoxybenzyl]-N- [2- (4-methoxyphenoxy) pyridin-3-yl]Acetamide (2d)Synthesis of (2)

The desired product (2d) is obtained from (2c) according to general step "B".

e) Synthesis of N- [2- (2-fluoroethoxy) -5-methoxybenzyl ] -N- [2- (4-methoxyphenoxy) pyridin-3-yl ] acetamide (2e)

According to general procedure "W", the desired product 2e was obtained from 0.3mmol (64.3mg) of 2- (4-methoxyphenoxy) pyridin-3-amine (J.org.chem.; 60; 16; 1995; 4991-4994) and 58.9mg (0.3mmol) of 1e in a yield of 76% (100 mg).

MS-ESI：441(M⁺+1，100)(Aldrich)

Elemental analysis:

calculated values: c65.44% H5.72% N6.36%

Measured value: c65.42% H5.71% N6.37%

Example 3

a) Synthesis of N- [2- (4-iodophenoxy) pyridin-3-yl ] -N- { 5-methoxy-2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy ] benzyl } acetamide (3a)

According to general procedure "W", the desired product 3a was obtained from 449mg of 5-methoxy-2- [2- (tetrahydro-2H-pyran-2-oxy) ethoxy ] benzaldehyde (EP1894915a1) and 500mg of 2- (4-iodophenoxy) pyridin-3-amine j.chem.soc. (1931), 529, 533 in 75% yield (747 mg).

MS-ESI：619(M⁺+1，100)。

Elemental analysis:

calculated values: c54.38% H5.05% N4.53%

Measured value: c54.38% H5.05% N4.53%

b) N- [2- (2-hydroxyethoxy) -5-methoxybenzyl ] -N- [2- (4-iodophenoxy) pyridin-3-yl ] acetamide (3b)

The expected product 3b was obtained from 3a (707mg, 1.14mmol) in 75% yield (459mg) according to general procedure "Z".

MS-ESI：535(M⁺+1，100)。

Elemental analysis:

calculated values: c51.70% H4.34% N5.24%

Measured value: c51.72% H4.35% N5.23%

c) Synthesis of 2- [2- ({ acetyl [2- (4-iodophenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] ethyl methanesulfonate

The desired product 3c was obtained from 3b (431mg, 0.81mmol) in a yield of 96% (494mg) according to general procedure "I".

MS-ESI：613(M⁺+1，100)。

Elemental analysis:

calculated values: c47.07% H4.11% N4.57%

Measured value: c47.10% H4.12% N4.56%

d)N-[2-([¹⁸F]2-fluoroethoxy) -5-methoxybenzyl]-N- [2- (4-iodophenoxy) pyridin-3-yl]Synthesis of acetamide (3d)

The desired product (3d) is obtained from (3c) according to general step "B".

e) Synthesis of N- [2- (2-fluoroethoxy) -5-methoxybenzyl ] -N- [2- (4-iodophenoxy) pyridin-3-yl ] acetamide (3e)

According to general procedure "W", the desired product 3e was obtained from 0.23mmol (71mg) of 2- (4-iodophenoxy) pyridin-3-amine j.chem.soc. (1931), 529, 533 and 45.1mg (0.23mmol) of 1e in 37% yield (37,2 mg).

MS-ESI：537(M⁺+1，100)。

Elemental analysis:

calculated values: c51.51% H4.13% N5.22%

Measured value: c51.53% H4.14% N5.21%

Example 4

a) Synthesis of N- [2- (2-fluorophenoxy) pyridin-3-yl ] -N- { 5-methoxy-2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy ] benzyl } acetamide (4a)

According to general procedure W, the expected product 4a was obtained from 0.25g (1.22mmol)2- (4-fluorophenoxy) pyridin-3-Amine (ABCR) and 342mg (1.17mmol) 5-methoxy-2- [2- (tetrahydro-2H-pyran-2-oxy) ethoxy ] benzaldehyde (EP1894915A1) in 66% yield (412 mg).

MS-ESI：511(M⁺+1，100)。

Elemental analysis:

calculated values: c65.87% H6.12% N5.49%

Measured value: c65.85% H6.11% N5.49%

b) Synthesis of N- [2- (2-fluorophenoxy) pyridin-3-yl ] -N- [2- (2-hydroxyethoxy) -5-methoxybenzyl ] acetamide (4b)

The expected product 4b was obtained from 4a (200mg, 0.39mmol) in 84% yield (140mg) according to general procedure "Z".

MS-ESI：427(M⁺+1，100)。

Elemental analysis:

calculated values: c65.87% H6.12% N5.49%

Measured value: c65.85% H6.11% N5.49%

c) Synthesis of 2- [2- ({ acetyl [2- (2-fluorophenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] ethyl methanesulfonate (4c)

The expected product 4c was obtained from 4b (122mg, 0.29mmol) in 71% yield (102mg) according to general procedure "I".

MS-ESI：505(M⁺+1，100)。

Elemental analysis:

calculated values: c57.13% H4.99% N5.55%

Measured value: c57.15% H5.00% N5.56%

d)N-[2-(2-[¹⁸F]Fluoroethoxy) -5-methoxybenzyl]-N- [2- (2-fluorophenoxy) pyridin-3-yl]Synthesis of acetamide (4d)

The desired product (4d) is obtained from 4c according to general procedure "B".

e) Synthesis of N- [2- (2-fluoroethoxy) -5-methoxybenzyl ] -N- [2- (2-fluorophenoxy) pyridin-3-yl ] acetamide (4e)

According to general procedure "W", the expected product 4e is obtained from 103mg (0.5mmol) of 2- (4-fluorophenoxy) pyridin-3-Amine (ABCR) and 100mg (0.5mmol) of 1e in 74% yield (159 mg).

MS-ESI：429(M⁺+1，100)。

Elemental analysis:

calculated values: c64.48% H5.18% N6.54%

Measured value: c64.47% H5.19% N6.53%

Example 5

a) Synthesis of N- [2- (2, 3-dimethylphenoxy) pyridin-3-yl ] -N- { 5-methoxy-2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy ] benzyl } acetamide (5a)

According to general procedure W, 250mg (1,17mg)2- (2, 3-dimethylphenoxy) pyridin-3-Amine (ABCR) and 327mg (1,17mg) 5-methoxy-2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy ] benzaldehyde (EP1894915A1) were converted. The desired product 5a (442mg) was obtained in 73% yield.

MS-ESI：621(M⁺+1，100)。

Elemental analysis:

calculated values: c69.21% H6.97% N5.38%

Measured value: c69.20% H6.98% N5.37%

b) Synthesis of N- [2- (2, 3-dimethylphenoxy) pyridin-3-yl ] -N- [2- (2-hydroxyethoxy) -5-methoxybenzyl ] acetamide (5b)

The expected product 5b was obtained from 5a (200mg, 0.38mmol) in 73% yield (122mg) according to general procedure "Z".

MS-ESI：437(M⁺+1，100)。

Elemental analysis:

calculated values: c68.79% H6.47% N6.42%

Measured value: c68.77% H6.46% N6.43%

c) Synthesis of 2- [2- ({ acetyl [2- (2, 3-dimethylphenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] ethyl methanesulfonate (5c)

According to general procedure "I", the desired product 5c was obtained from 4b (105mg, 0.24mmol) in a yield of 60% (74 mg).

MS-ESI：515(M⁺+1，100)。

Elemental analysis:

calculated values: c60.69% H5.88% N5.44%

Measured value: c60.68% H5.89% N5.43%

d) Synthesis of N- [2- (2, 3-dimethylphenoxy) pyridin-3-yl ] -N- [2- (2- [18F ] fluoroethoxy) -5-methoxybenzyl ] acetamide (5d)

The desired product (5d) is obtained from 5c according to general procedure "B".

e) Synthesis of N- [2- (2, 3-dimethylphenoxy) pyridin-3-yl ] -N- [2- (2-fluoroethoxy) -5-methoxybenzyl ] acetamide (5e)

According to general procedure "W", the desired product 5e was obtained from 108mg (0.5mg)2- (2, 3-dimethylphenoxy) pyridin-3-Amine (ABCR) and 100mg (0.5mmol)1e in a yield of 17% (38 mg).

MS-ESI：439(M⁺+1，100)(Aldrich)

Elemental analysis:

calculated values: c68.48% H6.21% N6.39%

Measured value: c68.46% H6.22% N6.38%

Example 6

a) Synthesis of N- { 5-methoxy-2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy ] benzyl } -N- (2-phenoxypyridin-3-yl) acetamide (6a)

According to general procedure W, 244mg (1.31mmol) of 2- (phenoxy) pyridin-3-amine (j.med.chem. (2002), 45, 23, 5182) and 367mg (1.31mmol) of 5-methoxy-2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy ] benzaldehyde (EP1894915a1) are converted. The desired product 6a was obtained in 50% yield (322 mg; 648 micromoles).

MS-ESI：492(M⁺+1，100)。

Elemental analysis:

calculated values: c68.28% H6.55% N5.69%

Measured value: c68.27% H6.56% N5.68%

b) Synthesis of N- [2- (2-hydroxyethoxy) -5-methoxybenzyl ] -N- (2-phenoxypyridin-3-yl) acetamide (6b)

The expected product 6b (438. mu. mol; 179mg) was obtained according to general procedure "Z" from 6a (295mg, 0.6mmol) in 73% yield.

MS-ESI：409(M⁺+1，100)。

Elemental analysis:

calculated values: c67.63% H5.92% N6.86%

Measured value: c67.62% H5.93% N6.85%

c) Synthesis of 2- (2- { [ acetyl (2-phenoxypyridin-3-yl) amino ] methyl } -4-methoxyphenoxy) ethyl methanesulfonate (6c)

According to general procedure "I", the desired product 6c was obtained from 6b (130mg, 0.32mmol) in 94% yield (146mg, 0.3 mmol).

MS-ESI：487(M⁺+1，100)。

Elemental analysis:

calculated values: c59.25% H5.39% N5.76%

Measured value: c59.27% H5.40% N5.77%

d)N-[2-([¹⁸F]2-fluoroethoxy) -5-methoxybenzyl]Synthesis of (E) -N- (2-phenoxypyridin-3-yl) acetamide (6d)

The desired product (6d) was obtained from 6c according to general procedure "B".

e) Synthesis of N- [2- (2-fluoroethoxy) -5-methoxybenzyl ] -N- (2-phenoxypyridin-3-yl) acetamide (6e)

According to general procedure "W", the desired product 6e was obtained from 244mg (1.31mmol)2- (phenoxy) pyridin-3-amine (j.med. chem. (2002), 45, 23, 5182) and 260mg (1.31mmol)1e in 82% yield (442 mg).

MS-ESI：411(M⁺+1，100)(Aldrich)

Elemental analysis:

calculated values: c67.31% H5.65% N6.83%

Measured value: c67.30% H5.66% N6.82%

Example 7

a) Synthesis of 2- [4- (2-tetrahydropyranyloxy-ethoxy) -phenoxy ] -3-nitro-pyridine (7a)

The desired product 7a was synthesized according to the modified procedure of Alsaidi et al (Synthesis; 11; 1980; 921) -924) using 2-chloro-3-nitro-pyridine (Aldrich) and 4- (2-tetrahydropyranyloxy-ethoxy) -phenol (J.Med.chem. (1998), 41, 9, 1540) -1554. The yield of the desired product 7a was 76%.

MS-ESI：361(M⁺+1，100)。

Elemental analysis:

calculated values: c59.99% H5.59% N7.77%

Measured value: c60.00% H5.58% N7.75%

b)2- [4- (2-tetrahydropyranyloxy-ethoxy) -phenoxy ] -pyridin-3-ylamine (7b)

The expected product 7b (526 mg; 1.6mmol) was obtained from 7a (722 mg; 2.0mmol) according to general procedure "L2".

MS-ESI：330(M⁺+1，100)。

Elemental analysis:

calculated values: c65.44% H6.71% N8.48%

Measured value: c65.42% H6.70% N8.47%

c) Synthesis of N- (2, 5-dimethoxybenzyl) -N- (2- {4- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy ] phenoxy } pyridin-3-yl) propanamide (7c)

MS-ESI：537(M⁺+1，100)。

Elemental analysis:

calculated values: c67.15% H6.76% N5.22%

Measured value: c67.12% H6.75% N5.21%

According to general procedure W, except that no acetic anhydride was used, propionyl chloride was used, the desired product 7c (436mg) was obtained from 7b (1,21 mmol; 400mg) and 2, 5-dimethoxy-benzaldehyde (Aldrich). The yield of the desired product was 67% (0.81 mmol).

d) Synthesis of N- (2, 5-dimethoxybenzyl) -N- (2- {4- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy ] phenoxy } pyridin-3-yl) propanamide (7d)

The expected product 7d was obtained from 7c (350mg, 0.65mmol) in 75% yield (0.49 mmol; 221mg) according to general procedure "Z".

MS-ESI：453(M⁺+1，100)。

Elemental analysis:

calculated values: c66.36% H6.24% N6.19%

Measured value: c66.36% H6.24% N6.19%

e) Synthesis of 2- [4- ({3- [ (2, 5-dimethoxybenzyl) (propionyl) amino ] pyridin-2-yl } oxy) phenoxy ] ethyl 4-methylbenzenesulfonate (7e)

MS-ESI：607(M⁺+1，100)。

Elemental analysis:

calculated values: c63.35% H5.65% N4.62%

Measured value: c63.33% H5.65% N4.63%

According to general procedure K, the expected product 7e (0.26 mmol; 158mg) is obtained from 7d (0.33 mmol; 150mg) in a yield of 75%.

f) N- (2, 5-dimethoxybenzyl) -N- {2- [4- (2-, [ solution ]¹⁸F]Fluoroethoxy) phenoxy]Synthesis of pyridin-3-yl } propionamide (7f)

The desired product (7f) is obtained from (7e) according to general procedure "B".

g) Synthesis of N- (2, 5-dimethoxybenzyl) -N- {2- [4- (2-fluoroethoxy) phenoxy ] pyridin-3-yl } propanamide (7g)

According to general procedure "A", 7g (48 mg; 0.106mmol) of the expected product are obtained from 7f (0.156 mmol; 94mg) in a yield of 68%.

MS-ESI：455(M⁺+1，100)。

Elemental analysis:

calculated values: c66.07% H5.99% N6.16%

Measured value: c66.07% H5.99% N6.16%

Biology of the species

It is an object of the present invention to find an improved F-18 labelled compound over the prior art which can be used for the treatment of cancer by targeting a peripheral benzodiazepine, also known as 18kDa translocation protein (TSPO)PET imaging of the receptor (PBR) detects activated microglia. The data of the present invention indicate that the tracer is compatible with the known tracer [2 ], [2 ]¹⁸F]-FEDAA1106(3) and [, [2 ]¹⁸F]-DPA-714(1.2) in a pharmaceutically acceptable carrier¹⁸F]2d and [2 ]¹⁸F]5d surprisingly showed an improved signal to background ratio in kainic acid induced brain lesions in rats.

0.264MBq 2 is intravenously injected into each animal¹⁸F]-2d and 0.268MBq [ solution ]¹⁸F]After-5 d2. Healthy male NMRI mice (28.3-35.6g body weight, n-3 at each time point) were studied at 5, 30, 60 and 180/240min¹⁸F]2d and [2 ]¹⁸F]-5d biodistribution. By the time point indicated, urine and feces were collected quantitatively. At each time point, mice were sacrificed and tissues removed. Analysis in a gamma counter¹⁸F]Radioactivity (tables 1.1, 2.1 and 1.2, 2.2).

[¹⁸F]2d represents [2 ]¹⁸F]High initial brain uptake of radioactivity (1.37 ± 0.04% injected dose/g at 2min p.i.), and high initial elimination of approximately 72% of the radioactivity from the brain at 30min p.i. (0.37 ± 0.04% injected dose/g; fig. 1.1), with a 2min/30min ratio of 3.7 (table 3). Overall, the amount of radiation in the blood and brain decreased over the time period studied. No relevant radioactive bone resorption was detected (2.3% injected dose/g at 180 min). A large amount of radioactivity accumulates in organs with known constitutive PBR expression (e.g. lung, heart, adrenal glands).

The radioactivity was excreted mainly through urine (13.09 ± 1.33% injected dose of urine and 0.59 ± 0.61% injected dose of feces at 180min p.i. over the observed time period) (table 1.1).

[¹⁸F]-5d represents [2 ]¹⁸F]High initial brain uptake of radioactivity (1.61 ± 0.23% injected dose/g at 2min p.i.), and high initial elimination of approximately 73% of the radioactivity from the brain at 30min p.i. (0.44 ± 0.15% injected dose/g; fig. 1.2), with a 2min/30min ratio of 3.7 (table 3). Overall, the amount of radiation in the blood and brain decreased over the time period studied. No relevant radioactive bone resorption was detected (2.6% injected dose/g at 240 min). A large amount of radioactivity accumulates in organs with known constitutive PBR expression (e.g. lung, heart, adrenal glands).

The radioactivity was excreted mainly through urine (at 240min p.i., urine 15.24 ± 1.25% injected dose, feces 0.74 ± 1.01% injected dose) over the period observed (table 1.2).

Using rat kainic acid induced epilepsy model and each sham control,isolated observation [2 ]¹⁸F]2d and [2 ]¹⁸F]-5d accumulation. Briefly, epilepsy was induced in rats by i.p. injection of kainic acid. On the 8 th day after the start of the kainic acid treatment, the dosage of 25.8 to 35.8MBq (about 1.0. mu.g) per rat is set¹⁸F]2d and [2 ]¹⁸F]5d into the tail vein of rats and their sham-treated controls (replacement of kainic acid with PBS). After 30 minutes of intravenous injection, the rats were sacrificed and the brains were removed, snap frozen and cross-sectioned in a cryostat. Sections were exposed overnight on PhosphoImager (PhosphoImager) plates. The resulting autoradiographic signals were analyzed qualitatively and quantitatively (FIGS. 2.1A and C, 2.2A and C). After exposure, sections were immunohistochemically stained with Ox-42 antibody (anti-CD 11b/c) to confirm kainic acid-induced microglial activation (fig. 2.1D and H, 2.2D and H). As observed by autoradiography of kainic acid treated rats, the signal was predominantly located in the hippocampus, which matched the immunohistochemical signal (fig. 2.1D-E and fig. 2.2D-E). To determine [2 ]¹⁸F]2d and [2 ]¹⁸F]-5d binding specificity, co-injection of [2 ] respectively to kainic acid-treated rats¹⁹F]-2e and [2 ]¹⁹F]-5 e. Significantly reduced autoradiographic signals were obtained from the brain regions of each of these rats (FIGS. 2.1B and 2.2B), while microglial activation in these brain sections could be confirmed by Ox-42 staining (FIGS. 2.1F-G and 2.2F-G). The sham-treated control received only [2 ]¹⁸F]2d or [2 ]¹⁸F]Injection at-5 d, but showed no significant autoradiographic signal in hippocampus or any other brain regions, even though those regions had constitutive PBR expression (fig. 2.1C and 2.2C). Immunohistochemistry confirmed the absence of activated microglia (FIGS. 2.1H-I and 2.2H-I). The autoradiographic signal in the ventricles was due to the known constitutive expression of PBR in ependymal and choroid plexus cells.

The autoradiographic signal was quantified. The signal intensity of the hippocampal Region (ROI) of interest was measured and compared to the ROI of the cerebellum, which was used as a reference region. The signal to background ratio is expressed as the hippocampal/cerebellar ratio (Table 3, FIG. 3), and is compared to [ [ alpha ] ] [, [ alpha ] ]¹⁸F]FEDAA1106 (1.2. + -. 0.2) and [, [2 ]¹⁸F]DPA-714 (2.4. + -. 0.5) vs, 5d (3.0. + -. 0.9)And 5e (5.6. + -. 1.8) are higher.

Surprisingly, the [ alpha ], [¹⁸F]2d and [2 ]¹⁸F]The signal-to-background ratio caused by-5 d and their elimination from the brain are superior to those of the known substance [ alpha ], [¹⁸F]-FEDAA1106(3) and [, [2 ]¹⁸F]DPA-714(1.2) (Table 3), whereas all four compounds are not related to CBR (Central diazepine)Receptor) to bind high affinity PBR ligands (table 4).

Table 1.1: injection [2 ]¹⁸F]After-2 d, the transurethral and fecal discharge in a normal mouse as detected by a gamma counter¹⁸F]Radioactivity, expressed as% injected dose.

Table 1.1: % injected dose (attenuation correction)

Time/organ:	2min	5min	30min	60min	180min
						urine collection device	0.02±0.01	0.02±0.01	1.72±0.08	4.21±0.39	13.09±1.33
Excrement and urine	0.00±0.00	0.02±0.03	0.01±0.00	0.03±0.03	0.59±0.61

Table 1.2: injection [2 ]¹⁸F]After-5 d, the transurethral and fecal discharge in the normal mouse as detected by the gamma counter¹⁸F]Radioactivity, expressed as% injected dose.

Table 1.2: % injected dose (attenuation correction)

Time/organ:	2min	5min	30min	60min	240min
						urine collection device	0.02±0.02	0.04±0.00	2.33±1.20	4.21±0.97	15.24±1.25
Excrement and urine	0.00±0.00	0.00±0.00	0.03±0.02	0.04±0.02	0.74±1.01

Table 2.1: injection [2 ]¹⁸F]In each organ detected by the gamma counter in the normal mouse at a different time point after-2 d¹⁸F]The biodistribution of radioactivity, expressed as% injected dose/g (n-3 per time point). Uptake of the tracer in different organs is consistent with the known local constitutive expression of PBR.

Table 2.1: % injected dose/g (attenuation correction)

FIG. 2.2: injection [2 ]¹⁸F]In each organ detected by the gamma counter in the normal mouse at a different time point after-5 d¹⁸F]The biodistribution of radioactivity, expressed as% injected dose/g (n-3 per time point). Uptake of the tracer in different organs is consistent with the known local constitutive expression of PBR.

Table 2.2: % injected dose/g (attenuation correction)

Time/organ:	2min	5min	30min	60min	240min
						spleen	1.40±0.06	3.25±0.15	5.68±0.59	5.79±0.10	3.02±0.25
Liver disease	1.51±0.38	2.19±.31	3.52±1.35	2.35±0.35	1.76±0.23
						Kidney (Kidney)	6.15±1.95	8.53±1.50	9.53±0.82	9.57±0.76	6.84±0.69
Lung (lung)	65.87±15.87	45.38±5.54	9.83±1.66	6.46±1.07	3.42±0.73
						Bone	1.02±0.31	1.41±0.19	2.05±0.08	1.69±0.26	2.59±0.56
Heart and heart	17.21±1.43	18.45±1.69	7.53±2.41	5.76±0.87	2.21±0.24
						Brain	1.61±0.23	1.13±0.22	0.44±0.51	0.34±0.06	0.32±0.08
Fat	0.24±0.08	0.24±0.03	0.61±0.26	3.27±0.30	0.86±0.10
						Thyroid gland	3.97±1.12	4.25±0.79	3.81±0.42	3.21±0.75	2.50±0.15
Muscle	1.23±0.27	1.89±0.32	2.14±0.31	2.13±0.21	1.32±0.11
						Skin(s)	0.52±0.02	0.79±0.07	1.23±0.21	1.39±0.10	1.47±0.06
Blood, blood-enriching agent and method for producing the same	2.75±0.40	2.13±0.23	0.80±0.17	0.75±0.01	0.60±0.07
						Stomach (stomach)	2.03±1.05	3.04±0.49	3.01±0.70	4.21±0.25	3.43±0.54
Testis	0.50±0.01	0.71±0.10	0.75±0.19	0.90±0.10	0.94±0.12
						Adrenal gland	9.90±1.17	28.94±11.26	12.31±0.43	16.66±2.86	13.93±6.07
Sausage	0.77±0.24	1.42±0.02	2.48±0.78	3.31±0.16	3.96±0.16
						Pancreas (pancreas)	1.54±0.34	2.37±0.56	2.46±0.19	2.34±0.48	1.41±0.22

Table 3: [¹⁸F]-2d、[¹⁸F]-5d、[¹⁸F]-FEDAA1106(3) and [, [2 ]¹⁸F]Comparison of the different parameters of DPA-714(1.2)

Table 3:

table 4: [¹⁹F]-2e、[¹⁹F]-5e、[¹⁹F]-FEDAA1106 and [2 ]¹⁹F]Comparison of different parameters of the DPA-714

Table 4:

in particular, the invention relates to

1. The compounds of formula I, including all isomeric forms of said compounds, including but not limited to enantiomers and diastereomers and racemic mixtures, and any pharmaceutically acceptable salts, esters, amides, complexes, or prodrugs thereof,

wherein

At each occurrence, R¹And R²Independently and independently selected from (G)³) Aryl, substituted (G)³) Aryl group, (G)³-(C₁-C₈) Alkyl) aryl, (G)³-(C₁-C₈) Alkoxy) aryl, (G)³-(C₂-C₈) Alkynyl) aryl, (G)³-(C₂-C₈) Alkenyl) aryl, substituted (G)³-(C₁-C₈) Alkyl) aryl, substituted (G)³-(C₁-C₈) Alkoxy) aryl, substituted (G)³-(C₂-C₈) Alkynyl) aryl and substituted (G)³-(C₂-C₈) Alkenyl) aryl;

at each occurrence, G¹、G²And G³Independently and independently selected from the group consisting of hydrogen and L,

provided that the compound of formula I comprises exactly one L;

l is selected from R³、[¹⁸F]Fluorine and [2 ]¹⁹F]Fluorine;

R³is a leaving group;

wherein n is an integer of 0 to 6.

2. A compound according to 1, wherein R³Is selected from-I⁺(aryl) (X)^-)、-I⁺(heteroaryl) (X)^-) Nitro, -N⁺(Me)₃(X^-) Halogen, in particular chlorine, bromine and iodine, mesyloxy, tosyloxy, trifluoromethylsulfonyloxy, nonafluorobutylsulfonyloxy, (4-bromo-phenyl) sulfonyloxy, (4-nitro-phenyl) sulfonyloxy, (2-nitro-phenyl) sulfonyloxy, (4-isopropyl-phenyl) sulfonyloxy, (2, 4, 6-tri-isopropyl-phenyl) sulfonyloxy, (2, 4, 6-trimethyl-phenyl) sulfonyloxy, (4-tert-butyl-phenyl) sulfonyloxy and (4-methoxy-phenyl) sulfonyloxy.

3. A compound according to 2, wherein X^-Selected from the group consisting of inorganic acid anions and organic acid anions.

4. A compound according to one of 3, wherein X^-Selected from CF₃S(O)₂O^-、C₄F₉S(O)₂O^-、CF₃COO^-、H₃CCOO^-Iodine and iodine yinIons, bromide anions, chloride anions, perchlorate anions (ClO)₄ ^-) And phosphate anions.

5. A compound according to any one of the preceding claims, selected from:

2- [2- ({ acetyl [2- (4-fluorophenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] ethyl methanesulfonate, or

2- [2- ({ acetyl [2- (4-iodophenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] ethyl methanesulfonate, or

2- (2- { [ acetyl (2-phenoxypyridin-3-yl) amino ] methyl } -4-methoxyphenoxy) ethyl methanesulfonate, or

2- [2- ({ acetyl [2- (2-fluorophenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] ethyl methanesulfonate, or

2- [2- ({ acetyl [2- (4-chlorophenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] ethyl methanesulfonate, or

2- [2- ({ acetyl [2- (4-methoxyphenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] ethyl methanesulfonate, or

3- [2- ({ acetyl [2- (4-fluorophenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] propyl 4-methylbenzenesulfonate, or

3- [2- ({ acetyl [2- (4-iodophenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] propyl 4-methylbenzenesulfonate, or

3- [2- ({ acetyl [2- (phenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] propyl 4-methylbenzenesulfonate, or

3- [2- ({ acetyl [2- (2-fluorophenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] propyl 4-methylbenzenesulfonate, or

3- [2- ({ acetyl [2- (4-chlorophenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] propyl 4-methylbenzenesulfonate, or

3- [2- ({ acetyl [2- (4-methoxyphenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] propyl 4-methylbenzenesulfonate.

6. A compound of the formula

2- [2- ({ acetyl [2- (4-fluorophenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] ethyl methanesulfonate.

7. A compound of the formula

2- [2- ({ acetyl [2- (2-fluorophenoxy) pyridin-3-yl ] amino } methyl) -4-methoxyphenoxy ] ethyl methanesulfonate.

8. A compound according to any one of 1 to 4, wherein L is not fluorine, particularly not [2 ]¹⁸F]Fluorine and [2 ]¹⁹F]Fluorine.

9. A compound according to any one of 1 to 4, wherein L is [ [ solution ] ], [ solution ]¹⁸F]Fluorine; or root ofThe compound according to 5, 6 or 7, wherein the methanesulfonyloxy group and the toluenesulfonyloxy group consist of [, ]¹⁸F]Fluorine is substituted.

10. A compound according to any one of 1 to 4, wherein L is [ [ solution ] ], [ solution ]¹⁹F]Fluorine; or the compound according to 5, 6 or 7, wherein the methanesulfonyloxy group and the toluenesulfonyloxy group are composed of¹⁹F]Fluorine is substituted.

11. A process for the synthesis of a compound as defined in 9 or 10, wherein a compound according to 1 to 8 is reacted with a F-fluorinating agent, wherein F ═ is¹⁸F or¹⁹F。

12. The process according to 11, wherein the F-fluorinating agent is a compound consisting of an F-anion, preferably selected from the group consisting of 4, 7, 13, 16, 21, 24-hexaoxa-1, 10-diazabicyclo [8.8.8]-hexacosane KF, i.e. the crown ether salt Kryptofix KF; KF; HF; KHF₂(ii) a CsF; NaF and a tetraalkylammonium salt of F, e.g., [2 ]¹⁸F]Tetrabutylammonium fluoride; and wherein F ═¹⁸F or¹⁹A compound of F.

13. A compound of formula VI, including all isomeric forms of said compound, including but not limited to enantiomers and diastereomers and racemic mixtures, and any pharmaceutically acceptable salts, esters, amides, complexes, or prodrugs thereof,

wherein

R¹⁰Is selected from (C)₁-C₆) Alkyl and hydrogen;

R¹⁶selected from hydrogen, halogen, trifluoromethyl and (C)₁-C₅) Alkyl, (C)₂-C₅) Alkynyl group), (C)₂-C₅) Alkenyl and (C)₁-C₅) An alkoxy group;

R¹²is selected from R¹³And hydrogen;

R¹³is a hydroxyl group;

with the proviso that the compound of formula VI contains exactly one R¹³；

At each occurrence, R⁴And R⁵Independently and independently selected from hydrogen, halogen, trifluoromethyl, (C)₁-C₅) Alkyl, (C)₂-C₅) Alkynyl, (C)₂-C₅) Alkenyl and (C)₁-C₅) An alkoxy group.

14. A process for the synthesis of a compound as defined in claim 9 or 10,

the method consists of the following steps:

formula V

Formula IV

-substitution of said compound of formula IV with a compound of formula VI

Including all isomeric forms of said compounds, including but not limited to enantiomers and diastereomers and racemic mixtures,

and any pharmaceutically acceptable salt, ester, amide, complex or prodrug thereof,

a is an integer of 0 to 5,

b is a leaving group, and B is a leaving group,

R¹⁰is selected from (C)₁-C₆) Alkyl and hydrogen;

R¹²is selected from R¹³And hydrogen;

R¹³is a hydroxyl group, and the hydroxyl group,

with the proviso that the compound of formula VI contains exactly one R¹³；

At each occurrence, R⁴And R⁵Independently and independently selected from hydrogen, halogen, trifluoromethyl, (C)₁-C₅) Alkyl, (C)₂-C₅) Alkynyl group), (C)₂-C₅) Alkenyl and (C)₁-C₅) An alkoxy group;

and

wherein the F-fluorinating agent is as defined by 10,

and wherein F ═¹⁸F or¹⁹F，

With the proviso that the compound of formula VI contains exactly one R¹³。

15. The process according to 14, wherein B is selected from the group consisting of iodo, bromo, chloro, mesyloxy, tosyloxy, trifluoromethylsulfonyloxy and nonafluorobutylsulfonyloxy.

16. A composition consisting of a compound according to any one of claims 1-10 and 13 and a pharmaceutically acceptable carrier or diluent.

17. The composition according to 16, wherein the compound is a compound according to 9.

18. The composition according to 16, wherein the compound is a compound according to 10.

19. The composition according to 16, wherein the compound is a compound according to 8.

20. The composition according to 16, wherein the compound is a compound according to 13.

21. A compound according to any one of claims 1 to 10, preferably a compound according to 8 or 9, 31 or 32, or a composition according to any one of claims 16, 17, 18, 19, 20 or 36, as a medicament or diagnostic agent or imaging agent.

22. Use of a compound according to any one of claims 1 to 10, preferably a compound according to 9, 10, 31 or 32, or a composition according to any one of claims 16, 17, 18, 19 or 20, for the manufacture of a medicament for the treatment and/or diagnosis and/or imaging of a disease of the Central Nervous System (CNS).

23. A compound according to 9, 31 or 32, or a composition according to 17 or 36, for use as a diagnostic or imaging agent, in particular for a disease of the central nervous system.

24. A kit consisting of a sealed vial containing a predetermined amount of a compound

a) According to the compounds of claim 5 or 8,

b) a compound according to 13, or

b) A compound of formulae V and VI as defined in any one of claims 14 to 15.

25. For detecting in vivo and in vitro benzodiazepines of patientThe presence of a receptor (translocator), preferably a method for imaging a central nervous system disorder in a patient, said method consisting of the steps of:

introducing into a patient a detectable amount of a compound according to 9, 32 or 33, or a composition according to 17 or 36,

Preferably, the central nervous system disease is alzheimer's disease, dementia, multiple sclerosis and amyotrophic lateral sclerosis.

26. A method of treating a central nervous system disorder, the method comprising the steps of: introducing an appropriate amount of a compound according to any one of 1-10 and 13, preferably a compound according to 9 or 10, to a patient.

Preferred central nervous system disorders are alzheimer's disease, dementia, multiple sclerosis and amyotrophic lateral sclerosis.

27. A method of monitoring the therapeutic effect of a therapeutic agent for treating a neurodegenerative disorder on a patient by imaging the patient being treated with an agent of a compound according to 9, 32 or 33.

The imaging method is preferably PET.

28. A method of monitoring response to treatment in a mammal having a neurodegenerative disorder, the method consisting of:

a) peripheral benzodiazepines using radiolabeling according to 9, 32 or 33The receptor ligands are imaged on the mammal and,

b) administering to a mammal in need thereof at least one agent suitable for treating a neurodegenerative disease,

c) imaging the mammal of step b) with the compound of a),

d) using peripheral benzodiazepines labelled by radioactivityThe signals obtained by the receptor ligands are used to compare the levels of CNS neurogenic inflammation.

29. The method according to 25, wherein steps a), b) and/or c) are repeated as desired.

26-28 is preferably selected from the group consisting of Alzheimer's disease, dementia, multiple sclerosis and amyotrophic lateral sclerosis.

30.9, 32 or 33 compounds and related derivatives, wherein¹⁸F is replaced by iodine (e.g., I-123). These compounds are suitable as imaging agents for SPECT applications.

31. Use of a compound according to 27 in SPECT applications.

32. A compound according to 9 having the structure

33. A compound according to 9 having the structure

34. A compound according to 32 and 33 as a diagnostic compound.

35. A compound according to 32 and 33 as diagnostic compound for PET imaging of alzheimer's disease.

36. A pharmaceutical or diagnostic composition comprising a compound according to 32 and 33.

37. The diagnostic composition according to 36 for PET imaging of alzheimer's disease.

38. A kit comprising a sealed vial comprising a compound according to 32 or 33.

39. A pharmaceutical or diagnostic composition comprising a compound according to 9.

40. A diagnostic composition comprising a compound according to claim 9 for PET imaging.

41. The diagnostic composition according to 40 for use in imaging of a neurological or CNS disease.

42. The diagnostic composition of 41, wherein said disease is Alzheimer's disease.

43. A method of synthesizing a compound according to 32 or 33 comprising the step of reacting a suitable precursor molecule with a F-18 fluorinating agent.

44. A method of synthesizing a compound according to 33 comprising fluorinating a compound having the formula with a suitable F-18 fluorinating agent.

Furthermore, the compounds according to 9, 10, 31 or 32, or the compositions according to 17 or 36, can be used in the diagnosis of rheumatoid arthritis. In a preferred embodiment, the method of diagnosing rheumatoid arthritis is PET imaging.

Claims

wherein

provided that the compound of formula I comprises exactly one L;

l is selected from R³、[¹⁸F]Fluorine and [2 ]¹⁹F]Fluorine;

R³is a leaving group;

wherein n is an integer of 0 to 6.

2. The compound of claim 1, wherein R³Is selected from-I⁺(aryl) (X)^-)、-I⁺(heteroaryl) (X)^-) Nitro, -N⁺(Me)₃(X^-) Halogen, in particular chlorine, bromine and iodine, mesyloxy, tosyloxy, trifluoromethylsulfonyloxy, nonafluorobutylsulfonyloxy, (4-bromo-phenyl) sulfonyloxy, (4-nitro-phenyl) sulfonyloxy, (2-nitro-phenyl) sulfonyloxy, (4-isopropyl-phenyl) sulfonyloxy, (2, 4, 6-tri-isopropyl-phenyl) sulfonyloxy, (2, 4, 6-trimethyl-phenyl) sulfonyloxy, (4-tert-butyl-phenyl) sulfonyloxy and (4-methoxy-phenyl) sulfonyloxy.

3. The compound of claim 2, wherein X^-Selected from the group consisting of inorganic acid anions and organic acid anions.

4. A compound according to claim 3, wherein X^-Selected from CF₃S(O)₂O^-、C₄F₉S(O)₂O^-、CF₃COO^-、H₃CCOO^-Iodine anion, bromine anion, chlorine anion, perchlorate anion (ClO)₄ ^-) And phosphate anions.

5. The compound of any one of the preceding claims, selected from:

6. A compound of the formula

7. A compound of the formula

8. The compound of any one of claims 1-4, wherein L is [ alpha ], [ beta ]¹⁸F]Fluorine; or the compound of claim 5, 6 or 7, wherein the methanesulfonyloxy group and the toluenesulfonyloxy group consist of¹⁸F]Fluorine is substituted.

9. The compound of any one of claims 1-4, wherein L is [ alpha ], [ beta ]¹⁹F]Fluorine; or the compound of claim 5, 6 or 7, wherein the methanesulfonyloxy group and the toluenesulfonyloxy group consist of¹⁹F]Fluorine is substituted.

10. A process for the synthesis of a compound as defined in claim 8 or 9, wherein a compound as defined in claims 1-7 is reacted with a F-fluorinating agent, wherein F ═ is¹⁸F or¹⁹F。

11. The process according to claim 10, wherein the F-fluorinating agent is a compound consisting of F-anions, preferably selected from the group consisting of 4, 7, 13, 16, 21, 24-hexaoxa-1, 10-diazabicyclo [8.8.8 ™ 8]-hexacosane KF, i.e. the crown ether salt Kryptofix KF; KF; HF; KHF₂(ii) a CsF; tetraalkylammonium salts of NaF and F, such as N (butyl) 4F (tetrabutylammonium fluoride); and wherein F ═¹⁸F or¹⁹A compound of F.

12. A compound of formula VI, including all isomeric forms of said compound, including but not limited to enantiomers and diastereomers and racemic mixtures, and any pharmaceutically acceptable salts, esters, amides, complexes, or prodrugs thereof,

wherein

R¹⁰Is selected from (C)₁-C₆) Alkyl and hydrogen;

R¹²is selected from R¹³And hydrogen;

R¹³is a hydroxyl group;

with the proviso that the compound of formula VI contains exactly one R¹³；

At each occurrence, R⁴And R⁵Independently and independently selected from hydrogen, halogen, trifluoromethyl, (C)₁-C₅) Alkyl, (C)₂-C₅) Alkynyl group), (C)₂-C₅) Alkenyl and (C)₁-C₅) An alkoxy group.

13. A method of synthesizing a compound as defined in claim 8 or 9, said method consisting of the steps of:

formula V

Formula IV

-substitution of said compound of formula IV with a compound of formula VI

Including all isomeric forms of said compounds, including but not limited to enantiomers and diastereomers and racemic mixtures, and any pharmaceutically acceptable salts, esters, amides, complexes or prodrugs thereof

a is an integer of 0 to 5,

b is a leaving group, and B is a leaving group,

R¹⁰is selected from (C)₁-C₆) Alkyl and hydrogen;

R¹²is selected from R¹³And hydrogen;

R¹³is a hydroxyl group, and the hydroxyl group,

with the proviso that the compound of formula VI contains exactly one R¹³；

and

wherein the F-fluorinating agent is as defined in claim 10,

and wherein F ═¹⁸F or¹⁹F，

With the proviso that the compound of formula VI contains exactly one R¹²It is a hydroxyl group.

14. The method of claim 14, wherein B is selected from the group consisting of iodo, bromo, chloro, methanesulfonyloxy, toluenesulfonyloxy, trifluoromethanesulfonyloxy, and nona-fluorobutylsulfonyloxy.

15. A composition consisting of a compound of any one of claims 1-9 and 12 and a pharmaceutically acceptable carrier or diluent.

16. A compound according to any one of claims 1 to 9 or a composition according to claim 15 as a medicament or diagnostic agent or imaging agent.

17. The compound of claim 8 or the composition of claim 15, wherein the composition comprises the compound of claim 8; it is useful as a diagnostic or imaging agent, particularly for central nervous system diseases.

18. A kit consisting of a sealed vial containing a predetermined amount of a compound

a) The compound of claim 5 or claims 1-4, with the proviso that L is not fluorine,

b) the compound of claim 12, or

b) Compounds of formulae V and VI as defined in any one of claims 12 to 13.

19. For detecting in vivo and in vitro benzodiazepines of patientA method of presence of a receptor (translocator), the method consisting of:

introducing into a patient a detectable amount of a compound of claim 8, or a composition of claim 15, wherein the composition comprises a compound of claim 8, and

detecting the compound or the composition by Positron Emission Tomography (PET).

20. A compound selected from compounds having the following structure:

21. a compound having the structure:

22. a compound having the structure:

23. a pharmaceutical or diagnostic composition comprising a compound as defined in claim 21 or 22.

24. A kit comprising a sealed vial containing a compound as defined in claim 21 or 22 or a pharmaceutical composition according to claim 23.